G. J. Lammers

CSF hypocretin/orexin levels in narcolepsy and other neurological conditions

Objective: To examine the specificity of low CSF hypocretin-1 levels in narcolepsy and explore the potential role of hypocretins in other neurologic disorders. Methods: A method to measure hypocretin-1 in 100 μL of crude CSF sample was established and validated. CSF hypocretin-1 was measured in 42 narcolepsy patients (ages 16–70 years), 48 healthy controls (ages 22–77 years,) and 235 patients with various other neurologic conditions (ages 0–85 years). Results: As previously reported, CSF hypocretin-1 levels were undetectably low (<100 pg/mL) in 37 of 42 narcolepsy subjects. Hypocretin-1 levels were detectable in all controls (224–653 pg/mL) and all neurologic patients (117–720 pg/mL), with the exception of three patients with Guillain–Barré syndrome (GBS). Hypocretin-1 was within the control range in most neurologic patients tested, including patients with AD, PD, and MS. Low but detectable levels (100–194 pg/mL) were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma, CNS infections, and GBS. Conclusions: Undetectable CSF hypocretin-1 levels are highly specific to narcolepsy and rare cases of GBS. Measuring hypocretin-1 levels in the CSF of patients suspected of narcolepsy is a useful diagnostic procedure. Low hypocretin levels are also observed in a large range of neurologic conditions, most strikingly in subjects with head trauma. These alterations may reflect focal lesions in the hypothalamus, destruction of the blood brain barrier, or transient or chronic hypofunction of the hypothalamus. Future research in this area is needed to establish functional significance.

Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives.

Summary Narcolepsy is characterized by excessive daytime sleepinessand abnormal manifestations of rapid eye movement sleep such as cataplexy. Theauthors review the clinical features of narcolepsy, including epidemiology,symptoms, diagnosis, and treatment, in detail. Recent findings show that aloss of hypocretin-producing neurons lies at the root of the signs andsymptoms of narcolepsy. The authors review the current state of knowledge onhypocretin anatomy, physiology, and function with special emphasis on theresearch regarding the hypocretin deficiency in narcolepsy, which may alsoexplain associated features of the disorder, such as obesity. Lastly, theydiscuss some future perspectives for research into the pathophysiology ofsleep/wake disorders, and the potential impact of the established hypocretindeficiency on the diagnosis and treatment ofnarcolepsy.

A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects.

BACKGROUND Subsequent nights with partial sleep restriction result in impaired glucose tolerance, but the effects on insulin sensitivity have not been characterized. OBJECTIVE The aim of this study was to evaluate the effect of a single night of partial sleep restriction on parameters of insulin sensitivity. RESEARCH DESIGN AND METHODS Nine healthy subjects (five men, four women) were studied once after a night of normal sleep duration (sleep allowed from 2300 to 0730 h), and once after a night of 4 h of sleep (sleep allowed from 0100 to 0500 h). Sleep characteristics were assessed by polysomnography. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp studies (from 1130 to 1430 h) with infusion of [6,6-(2)H(2)]glucose. RESULTS Sleep duration was shorter in the night with sleep restriction than in the unrestricted night (226 +/- 11 vs. 454 +/- 9 min; P< 0.0001). Sleep restriction did not affect basal levels of glucose, nonesterified fatty acids, insulin, or endogenous glucose production. Sleep restriction resulted in increased endogenous glucose production during the hyperinsulinemic clamp study compared to the unrestricted night (4.4 +/- 0.3 vs. 3.6 +/- 0.2 micromol x kg lean body mass(-1) x min(-1); P = 0.017), indicating hepatic insulin resistance. In addition, sleep restriction decreased the glucose disposal rate during the clamp (32.5 +/- 3.6 vs. 40.7 +/- 5.1 micromol x kg lean body mass(-1) x min(-1); P = 0009), reflecting decreased peripheral insulin sensitivity. Accordingly, sleep restriction decreased the rate of glucose infusion by approximately 25% (P = 0.001). Sleep restriction increased plasma nonesterified fatty acid levels during the clamp study (68 +/- 5 vs. 57 +/- 4 micromol/liter; P = 0.005). CONCLUSIONS Partial sleep deprivation during only a single night induces insulin resistance in multiple metabolic pathways in healthy subjects. This physiological observation may be of relevance for variations in glucoregulation in patients with type 1 and type 2 diabetes.

Normal hypocretin-1 levels in Parkinson's disease patients with excessive daytime sleepiness.

Sleep disturbances frequently occur in patients with PD.1 Sleep problems are often related to the disease itself (e.g., difficulties in maintaining sleep because of motor disabilities), but they can also occur secondary to treatment.1 Recently, attention has been focused on so-called “sleep-attacks” in PD, which can be induced by all dopaminomimetic drugs, including D2/3 selective agonists.2 Because the term sleep attack (implicating that the episodes occur without warning) applies only to the minority of episodes, we will use the term “excessive daytime sleepiness” (EDS). EDS induced by dopaminergic treatment in PD shares clinical and neurophysiologic characteristics with EDS seen in narcolepsy.3 Narcolepsy is a sleep disorder clinically characterized by EDS, cataplexy, hypnagogic hallucinations, and sleep paralysis, and is tightly linked to HLA DQB1*0602.4 Narcolepsy is caused by a deficiency in hypocretin neurotransmission (for a review, see Overeem et al.4). Hypocretin-1 and -2 are neuropeptides exclusively produced in the hypothalamus. …

Convergence of circadian and sleep regulatory mechanisms on hypocretin-1

Hypocretin is a potential regulator of sleep and wakefulness and its levels fluctuate with the day-night cycle with high levels during the animals activity period. Whether the daily fluctuations are driven endogenously or by external light cycles is unknown. We investigated the circadian and homeostatic regulation of hypocretin in the absence of environmental light cycles. To this purpose we performed repetitive samplings of cerebrospinal fluid in rats through implanted microcannulas in the cisterna magna and determined hypocretin-1 levels by radioimmunoassay. These experiments were also performed in rats that received a lesion of the suprachiasmatic nucleus (SCN), a major pacemaker for circadian rhythms in mammals. The results showed sustained rhythmicity of hypocretin in constant dim red light in control animals. SCN-lesioned animals showed no circadian rhythms in hypocretin and mean hypocretin levels were remarkably low. The results indicate that the SCN is indispensable for rhythmicity in hypocretin and induces a daily increase in hypocretin levels during the animals active phase. Additional sleep deprivation experiments were carried out to investigate homeostatic regulation of hypocretin. Hypocretin levels increased in response to sleep deprivation in both control and SCN-lesioned animals, demonstrating that sleep homeostatic control of hypocretin occurs independently from the SCN. Our data indicate that the circadian pacemaker of the SCN and sleep homeostatic mechanisms converge on one single sleep regulatory substance.

Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis

Idiopathic narcolepsy is associated with deficient hypocretin transmission. Narcoleptic symptoms have recently been described in paraneoplastic encephalitis with anti-Ma2 antibodies. The authors measured CSF hypocretin-1 levels in six patients with anti-Ma2 encephalitis, and screened for anti-Ma antibodies in patients with ideopathic narcolepsy. Anti-Ma autoantibodies were not detected in patients with idiopathic narcolepsy. Four patients with anti-Ma2 encephalitis had excessive daytime sleepiness; hypocretin-1 was not detectable in their cerebrospinal fluid, suggesting an immune-mediated hypocretin dysfunction.

CSF hypocretin levels in Guillain–Barré syndrome and other inflammatory neuropathies

CSF hypocretin-1 was measured in 28 Guillain–Barré syndrome (GBS), 12 Miller–Fisher syndrome, 12 chronic inflammatory demyelinating polyneuropathy (CIDP), and 48 control subjects. Seven GBS subjects had undetectably low hypocretin-1 levels (<100 pg/mL). Hypocretin-1 levels were moderately reduced in an additional 11 GBS, 5 Miller–Fisher syndrome, and 1 CIDP subject. Low levels in GBS occurred early in the disease and were associated with upper CNS level abnormalities.

Effects of startle and laughter in cataplectic subjects : a neurophysiological study between attacks

OBJECTIVES Cataplexy, when unequivocally present together with excessive daytime sleepiness, is diagnostic for narcolepsy. Unfortunately, it is difficult to induce cataplexy during consultation. In this study we tried to assess presumed subclinical expressions of cataplexy using neurophysiological tests. METHODS In this controlled explorative study, we studied 14 patients with a clear history of cataplexy and 12 matched controls using standard H-reflex, H/M ratios, audiospinal reflex, H-reflexes modulated by emotions and startle reflexes. RESULTS H-reflexes were attenuated during laughter in patients as well as controls. Startle reflexes were increased in patients. Audiospinal reflexes were not influenced. CONCLUSIONS The patterns found add relevant knowledge concerning pathophysiological mechanisms and involved brain areas in cataplexy, and may reflect subclinical expressions of cataplexy. The presumed specificity of the abolishment of H-reflexes during cataplectic attacks is questioned by our findings. The exaggerated startle reflex is in line with recent findings concerning involved brain areas in narcolepsy.

Patients Previously Treated for Nonfunctioning Pituitary Macroadenomas Have Disturbed Sleep Characteristics, Circadian Movement Rhythm, and Subjective Sleep Quality

CONTEXT AND OBJECTIVE Fatigue and excessive sleepiness have been reported after treatment of nonfunctioning pituitary macroadenomas (NFMA). Because these complaints may be caused by disturbed nocturnal sleep, we evaluated objective sleep characteristics in patients treated for NFMA. DESIGN We conducted a controlled cross-sectional study. SUBJECTS AND METHODS We studied 17 patients (8 women; mean age, 54 yr) in remission of NFMA during long-term follow-up (8 yr; range, 1-18 yr) after surgery (n = 17) and additional radiotherapy (n = 5) without comorbidity except for hypopituitarism and 17 controls matched for age, gender, and body mass index. Sleep was assessed by nocturnal polysomnography, sleep and diurnal movement patterns by actigraphy, and quality of life and subjective sleep characteristics by questionnaires. RESULTS Compared to controls, patients had reduced sleep efficiency, less rapid eye movement sleep, more N1 sleep, and more awakenings in the absence of excessive apnea or periodic limb movements. Actigraphy revealed a longer sleep duration and profound disturbances in diurnal movement patterns, with more awakenings at night and less activity during the day. Patients scored higher on fatigue and reported impaired quality of life. CONCLUSION Patients previously treated for NFMA suffer from decreased subjective sleep quality, disturbed distribution of sleep stages, and disturbed circadian movement rhythm. These observations indicate that altered sleep characteristics may be a factor contributing to impaired quality of life and increased fatigue in patients treated for NFMA.

Manipulation of skin temperature improves nocturnal sleep in narcolepsy

Objective: Besides excessive daytime sleepiness, disturbed nocturnal sleep is a major complaint of patients with narcolepsy. Previously, alterations in skin temperature regulation in narcoleptic patients have been shown to be related to increased sleepiness. This study tests the hypothesis that direct control of nocturnal skin temperature might be applied to improve the disturbed sleep of narcoleptic patients. Methods: Participants were eight patients (five males) diagnosed as having narcolepsy with cataplexy according to the ICSD-2 criteria, mean (SD) age 28.6 (6.4) years, range 18–35 years. During two nights, sleep was recorded polysomnographically while proximal and distal skin temperature were manipulated using a comfortable thermosuit that induced skin temperature to cycle slowly with an amplitude of only 0.4°C within the comfortable range normally observed during sleep. Logistic regression was used to evaluate the effect of skin temperature manipulation on the probability of occurrence of different sleep stages and nocturnal wakefulness. Results: Proximal skin warming significantly suppressed wakefulness and enhanced slow wave sleep (SWS). In contrast, distal skin warming enhanced wakefulness and stage 1 sleep at the cost of SWS and REM sleep. The optimal combination of proximal skin warming and distal skin cooling led to a 160% increase in SWS, a 50% increase in REM sleep and a 68% decrease in wakefulness, compared with the least beneficial combination of proximal skin cooling and distal skin warming. Interpretation: Subtle skin temperature manipulations under controlled conditions significantly improved the typical nocturnal sleep problems in narcolepsy.