Michael S. Aldrich

A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.

Reduced number of hypocretin neurons in human narcolepsy.

Murine and canine narcolepsy can be caused by mutations of the hypocretin (Hcrt) (orexin) precursor or Hcrt receptor genes. In contrast to these animal models, most human narcolepsy is not familial, is discordant in identical twins, and has not been linked to mutations of the Hcrt system. Thus, the cause of human narcolepsy remains unknown. Here we show that human narcoleptics have an 85%-95% reduction in the number of Hcrt neurons. Melanin-concentrating hormone (MCH) neurons, which are intermixed with Hcrt cells in the normal brain, are not reduced in number, indicating that cell loss is relatively specific for Hcrt neurons. The presence of gliosis in the hypocretin cell region is consistent with a degenerative process being the cause of the Hcrt cell loss in narcolepsy.

The Epworth Sleepiness Scale may not reflect objective measures of sleepiness or sleep apnea

Objective: To assess the validity of the Epworth Sleepiness Scale score (ES) as a measure of sleepiness among patients suspected or confirmed to have obstructive sleep apnea syndrome. Background: The ES is used with increasing frequency as a measure of excessive daytime sleepiness in part because several studies suggested that the ES correlates with mean sleep latency (MSL) on the Multiple Sleep Latency Test and with severity of sleep apnea among patients with that disorder. However, associations identified between the ES and other measures were not strong or consistent. Methods: The authors used regression models and retrospective data from a relatively large series of 237 patients to restudy how ES relates to MSL, to a simple self-rating of problem sleepiness (available for 141 patients), and to two polysomnographic measures of sleep apnea severity: the number of apneas or hypopneas per hour of sleep and the minimum recorded oxygen saturation. Results: The ES had a statistically significant association with self-rated problem sleepiness but not with MSL or measures of sleep apnea severity. Male gender, adjusted for potential confounding variables, had considerably more influence on the ES than did MSL or measures of sleep apnea severity. Conclusions: Our data suggest that the subjectively derived ES cannot be used as a surrogate for the objectively determined MSL.

Decreased striatal dopaminergic innervation in REM sleep behavior disorder.

Article abstract—REM sleep behavior disorder (RBD) is a possible herald of neurodegenerative disorders with parkinsonism. The authors determined the density of striatal dopaminergic terminals with [11C]dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic RBD and 19 age-appropriate controls. In subjects with RBD, there were significant reductions in striatal [11C]dihydrotetrabenazine binding, particularly in the posterior putamen.

Sleep apnea in patients with transient ischemic attack and stroke A prospective study of 59 patients

Although sleep apnea (SA) appears to be a cardiovascular risk factor, little is known about its frequency in patients with transient ischemic attack (TIA) and stroke.We prospectively studied 59 subjects (26 women and 33 men; mean age, 62 years) with stroke (n = 36) or TIA (n = 23) with the use of a standard protocol that included assessment of snoring and daytime sleepiness (Epworth Sleepiness Score [ESS]), a validated SA score (Sleep Disorders Questionnaire [SDQ-SA]), and a severity of stroke score (Scandinavian Stroke Scale [SSS]). SA was considered clinically probable (P-SA) when habitual snoring was associated with an ESS of >10 or when SDQ-SA score was >or=to32 in women and >or=to36 in men. Polysomnography (PSG) was obtained in 36 subjects (group 1) a mean of 12 days after TIA or stroke. In 23 subjects (group 2), PSG was not available (n = 11), refused (n = 10), or inadequate (n = 2). Clinical and PSG data were compared with those obtained in 19 age- and gender-matched control subjects. Groups 1 and 2 were similar in mean age (61 versus 64 years), type of event (36% versus 44% TIA), reported habitual snoring (58% versus 52%), and P-SA (58% versus 50%). PSG showed SA (Apnea-Hypopnea Index [AHI], >or=to10) in 25 of 36 subjects (69%). The proportion of subjects with SA was similar in the TIA and stroke groups (69% versus 70%) and was well above the frequency found in our control group (15%). An AHI of >or=to20 and a minimal oxygen saturation of <85% were each found in 20 of 36 subjects (55%). Gender and age did not correlate with severity of SA. Subjects with habitual snoring, P-SA, or severe stroke (SSS of <30) had a significantly higher AHI (p < 0.05). The sensitivity of P-SA for SA was 64%, and the specificity was 67%. We conclude that SA has a high frequency in patients in the acute phase of TIA and stroke and SA cannot be predicted reliably on clinical grounds alone but is more likely in patients with habitual snoring, abnormal SDQ-SA, or severe stroke. NEUROLOGY 1996;47: 1167-1173

Interictal spiking increases with sleep depth in temporal lobe epilepsy

Summary: Purpose: To test the hypothesis that deepening sleep activates focal interictal epileptiform discharges (IEDs), we performed EEG‐polysomnography in 21 subjects with medically refractory temporal lobe epilepsy.

Sleep-Disordered Breathing in Patients With Acute Supra- and Infratentorial Strokes: A Prospective Study of 39 Patients

BACKGROUND AND PURPOSE Although recent studies suggest a high prevalence of obstructive sleep apnea (OSA) in patients with acute stroke, a systematic characterization of sleep-disordered breathing based on the severity and topography of stroke has not been performed. METHODS We prospectively studied 39 noncomatose adult subjects (15 women, 24 men; mean age, 57 years) with a first acute stroke. Sleep history, cardiovascular risk factors, stroke severity as estimated by the Scandinavian Stroke Scale, and extent of stroke demonstrated on a computed tomographic or magnetic resonance imaging scan of the brain were assessed. Polysomnography was performed a mean of 10 days (range, 1 to 49 days) after stroke onset. Monitoring of breathing during wakefulness, non-rapid eye movement sleep, and rapid eye movement sleep included measurements of nasal/oral airflow, respiratory effort, and oxygen saturation. RESULTS Breathing was abnormal during wakefulness in 7 (18%) subjects and during sleep in 26 (67%). Obstructive sleep apnea (apnea-hypopnea index > 10) was found in 14 subjects, Cheyne-Stokes-like breathing was observed in 4, and a combination of obstructive sleep apnea and Cheyne-Stokes-like breathing was observed in 7. Sustained tachypnea and ataxic breathing were rare. No significant differences were found in age, body mass index, history of snoring or hypersomnia, or stroke topography or severity between subjects with and without sleep-disordered breathing. Prevalence and severity of breathing disturbances were also similar between patients with supratentorial stroke (n = 28) and those with infratentorial (n = 11) stroke. CONCLUSIONS Sleep-disordered breathing is frequent in patients with acute stroke, rarely has localizing value, and can also be found in patients with mild neurological deficits. Respiratory disturbances in stroke victims can be explained only in part by topography and extension of acute brain damage.

Reliability of sleep diaries for assessment of sleep/wake patterns.

Although sleep diaries are widely used in clinical and research settings, only a few studies have compared the subjective information recorded in these diaries to objective information about sleep recorded. The goal of this study was to determine if a sleep diary could be used to obtain reliable data about home sleep/wake patterns over a 24-hour period. Fifty subjects (25 narcoleptic and 25 matched control subjects) completed a sleep diary while undergoing 24-hour ambulatory polysomnographic monitoring. The percentage agreement between the subjective data recorded in the sleep diaries and polysomnographic data was acceptable (kappa = .87). Sensitivity and specificity were also high (92.3% and 95.6%). The sleep diary is a reliable instrument for collecting data about sleep/wake patterns, but should be used with caution when collecting data from subjects who are likely to take frequent daytime naps.

Usefulness of polysomnography in epilepsy patients

we reviewed the records of 63 adult epilepsy patients who underwent polysomnograms in our laboratory since 1985 to determine the indications for polysomnography and the results of testing. Reasons for referral included excessive daytime sleepiness, suspected obstructive sleep apnea (OSA), and characterization of nocturnal spells. The most common polysomnographic diagnosis was OSA, although we also found narcolepsy, insufficient sleep syndrome with possible idiopathic hypersomnolence, and previously unrecognized nocturnal seizures. We treated OSA with continuous positive airway pressure in 28 patients, 15 of whom were using the device at follow-up appointments. The majority of patients treated for OSA or other disorders reported an improvement in sleepiness or seizure control. Polysomnography, when indicated, is beneficial in epilepsy patients.

Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 IIIA

A 40-year-old male liver allograft recipient had neurological dysfunction and renal failure while his cyclosporin blood levels were in the therapeutic range; these features recurred on rechallenge. The hypothesis that this toxic effect might have resulted from abnormal metabolism of cyclosporin by liver cytochrome P-450 IIIA was investigated with the [14C]erythromycin breath test, which is a measure of this enzymes activity. P-450 IIIA activity was decreased compared with that in controls, including other liver transplant recipients. Pretreatment with rifampicin, an inducer of P-450 IIIA, increased enzyme activity. After treatment with rifampicin the patient could be rechallenged with cyclosporin at a dose almost twice that which had previously been toxic. The patient died during a second transplantation and the microsomal content of P-450 IIIA was found to be low in the first transplant.