Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat.

STUDY OBJECTIVES: Niemann-Pick type C (NPC) is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids. Symptoms include hepatosplenomegaly, vertical supranuclear saccadic palsy, ataxia, dystonia, and dementia. Some cases frequently display narcolepsy-like symptoms, including cataplexy which was reported in 26% of all NPC patients and was more often recorded among late-infantile onset (50%) and juvenile onset (38%) patients. In this current study, we examined CSF orexin levels in the 10 patients of NPC with and without cataplexy, which supports previous findings. METHODS: Ten patients with NPC were included in the study (5 males and 5 females). NPC diagnosis was biochemically confirmed in all 10 patients, from which 8 patients with NPC1 gene were identified. We compared CSF orexin levels among NPC, narcoleptic and idiopathic hypersomnia patients. RESULTS: Six NPC patients with cataplexy had low or intermediate orexin levels. In 4 cases without cataplexy, their orexin levels were normal. In 5 cases with Miglustat treatment, their symptoms stabilized or improved. For cases without Miglustat treatment, their conditions worsened generally. The CSF orexin levels of NPC patients were significantly higher than those of patients with narcolepsy-cataplexy and lower than those of patients with idiopathic hypersomnia, which was considered as the control group with normal CSF orexin levels. DISCUSSION: Our study indicates that orexin level measurements can be an early alert of potential NPC. Low or intermediate orexin levels could further decrease due to reduction in the neuronal function in the orexin system, accelerating the patients' NPC pathophysiology. However with Miglustat treatment, the orexin levels stabilized or improved, along with other general symptoms. Although the circuitry is unclear, this supports that orexin system is indeed involved in narcolepsy-cataplexy in NPC patients. CONCLUSION: The NPC patients with cataplexy had low or intermediate orexin levels. In the cases without cataplexy, their orexin levels were normal. Our study suggests that orexin measurements can serve as an early alert for potential NPC; furthermore, they could be a marker of therapy monitoring during a treatment.

Cerebrospinal fluid orexin-A levels in systemic lupus erythematosus patients presenting with excessive daytime sleepiness.

Objective Involvement of the hypothalamus is rare in patients with systemic lupus erythematosus (SLE). In this study, we measured cerebrospinal fluid (CSF) orexin-A levels in SLE patients with hypothalamic lesions to investigate whether the orexin system plays a role in SLE patients with hypothalamic lesions who present with excessive daytime sleepiness (EDS). Methods Orexin-A levels were measured in CSF from four patients with SLE who presented with hypothalamic lesions detected by MRI. Three patients underwent repeated CSF testing. All patients met the updated American College of Rheumatology revised criteria for SLE. Results Tests for serum anti-aquaporin-4 antibodies, CSF myelin basic protein and CSF oligoclonal bands were negative in all patients. All patients presented with EDS. Low to intermediate CSF orexin-A levels (92-180 pg/ml) were observed in three patients in the acute stage, two of whom (patients 1 and 2) underwent repeated testing and showed increased CSF orexin-A levels, reduced abnormal hypothalamic lesion intensities detected by MRI and EDS dissipation at follow-up. In contrast, CSF orexin-A levels were normal in one patient (patient 4) while in the acute stage and at follow-up, despite improvements in EDS and MRI findings. Patient 4 showed markedly increased CSF interleukin-6 levels (1130 pg/ml) and a slightly involved hypothalamus than the other patients. Conclusions Our findings suggest that the orexinergic system has a role in EDS in SLE patients with hypothalamic lesions. Furthermore, cytokine-mediated tissue damage might cause EDS without orexinergic involvement.

Hypocretin/orexin and narcolepsy: new basic and clinical insights.

Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis and hypnagogic hallucinations. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin ligand deficiency is found in a large majority of narcolepsy with cataplexy. Hypocretin ligand deficiency in human narcolepsy is probably due to the post-natal cell death of hypocretin neurones. Although a close association between human leucocyte antigen (HLA) and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proved. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO)-related disorder. The findings in symptomatic narcoleptic cases may have significant clinical relevance to the understanding of the mechanisms of hypocretin cell death and choice of treatment option. The discoveries in human cases lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid hypocretin-1 levels for 'narcolepsy with cataplexy' and 'narcolepsy due to medical condition'). As a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress.

Endovascular Treatment of Urgent Carotid Occlusion. Case selection & Technique.

SUMMARY: Emergency revascularization of acute carotid artery occlusion is still controversial.We treated 15 patients (13 men and two women, mean age of 67.3 years) with acute atherosclerotic carotid occlusion by endovascular procedures and evaluated the usefulness of this treatment. All of the patients were evaluated with emergency MRI and MRA before treatment. Intracranial tandem arterial occlusion due to distal embolism was observed in nine patients, and contralateral carotid stenosis (> 70%) was observed in seven. The mean NIHSS score of the patients was 15.4 +/- 7.4 (mean +/- SD) before treatment. Treatment modality included local intraarterial fibrinolysis (LIF), percutaneous transluminal angioplasty (PTA), and carotid artery stenting (CAS). A protective balloon was successfully placed in the distal carotid artery through the plaque before recanalization in seven patients. Three patients were treated with LIF+PTA, five with PTA+CAS, six with LIF+PTA+CAS, and one with PTA only. Successful recanalization of the carotid artery was obtained in 14 of the 15 patients, and distal tandem middle cerebral artery occlusion was also successfully recanalized in eight of the nine patients. GOS was four or five in eight patients (good outcome group) and 1-3 in seven patients (poor outcome group). Mean NIHSS score of the 15 patients was (6.9 +/- 7.4) after treatment. Preoperative NIHSS score (10.3 +/- 7.4) in the good outcome group was significantly lower than that (21.3 +/- 5.4) in the poor outcome group. The protective balloon technique, PTA with stenting, seems to be useful for acute revascularization of urgent carotid occlusion. Simultaneous treatment of the intracranial tandem occlusive lesion is essential to achieve good clini-cal results. Patients with acute carotid occlusion with NIHSS scores of less than 16 could be good candidates for this advanced treatment.

CSF hypocretin measures in patients with obstructive sleep apnea.

The majority of patients with narcolepsy-cataplexy were reported to have very low cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) levels. The hypocretin-1 levels of secondary excessive daytime sleepiness (EDS) disorders are not known. In this study, we found that CSF hypocretin levels in the patients with obstructive sleep apnea syndrome were within the control range. The low hypocretin levels seem to reflect only the presence of cataplexy and DR2 positive in narcoleptics but not EDS itself.

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.

Narcolepsy in a hypocretin/orexin-deficient chihuahua.

A two-year-old male chihuahua suffered attacks of muscle weakness and immobility, although it had no family history of paroxysmal attacks. No neurological or blood biochemical abnormalities were recorded when it was first examined. The attacks were typically elicited by stimulation, such as feeding, and a case of sporadic narcolepsy-cataplexy was therefore suspected. Treatment orally three times a day with 1 mg/kg imipramine, was effective in reducing the attacks. The concentration of hypocretin-1/orexin A in the dog's cerebrospinal fluid was less than 80 pg/ml (22.5 pmol/litre), compared with normal canine levels of 250 to 350 pg/ml (70.0 to 98.3 pmol/litre), supporting a diagnosis of hypocretin-deficient narcolepsy.

Undetectable levels of CSF hypocretin-1 (orexin-A) in two prepubertal boys with narcolepsy.

We report on two prepubertal narcoleptic boys with undetectable levels of hypocretin-1 (orexin-A) in their cerebrospinal fluid (CSF). The disease onset times were 6 and 8 years, and CSF was collected 8 and 20 months after the onset, respectively. The initial symptoms were excessive daytime sleepiness, cataplexy and disrupted nocturnal sleep. Both subjects are DRB1*1501 and DQB1*0602 positive. The measurement of CSF hypocretin-1 is valuable for the decisive diagnosis of narcolepsy and for selecting the type of treatment in prepubertal children. Our results suggest that a significant degree of hypocretin deficiency is already present at the disease onset.

Hypersomnia due to acute disseminated encephalomyelitis in a 5-year-old girl.

A 5-year-old girl suffering from hypersomnia due to acute disseminated encephalomyelitis (ADEM) is reported. Brain CT revealed a large low-density lesion involving the lentiform nucleus, posterior limb of the internal capsule, thalamus, posterior hypothalamus and midbrain in the left side. She was treated with intravenous dexamethazone. After the initial dose of dexamethazone, hypersomnia was dramatically and rapidly improved. A later brain CT study disclosed that the lesion in the brain disappeared. The brain lesion in this case involved the waking center in the brain, which was described by Von Economo. We concluded that hypersomnia in this case was due to ADEM involving the neural mechanism for maintaing wakefulness, probably in the thalamus and posterior hypothalamus. Repeat all night polysomnograpy in this case disclosed prolonged total sleep time and increased amount of stage 3-4 sleep in the hypersomniac state.

The effects of oral melatonin on the autonomic function in healthy subjects.

We investigated the influence of melatonin on the human autonomic functions by measuring muscle sympathetic nerve activity (MSNA). Five healthy male volunteers took 3 mg of melatonin, and their plasma melatonin concentration, blood pressure, heart rate, and burst rate of MSNA were then recorded. The peak level of melatonin concentration showed a marked interindividual variation. Blood pressure was reduced significantly, while heart rate and burst rate of MSNA did not change significantly. These results indicate that melatonin has a hypotensive effect on blood pressure, and the central cardiovascular regulatory mechanism such as lowering of the baroreflex setpoint would be involved in the effect.

Implication of dopaminergic mechanisms in the wake-promoting effects of amphetamine: a study of D- and L-derivatives in canine narcolepsy.

Using a canine model of narcolepsy and selective DA and NE uptake inhibitors, we have recently shown that DA uptake inhibition promotes wakefulness, while NE uptake inhibition inhibits rapid eye movement sleep and cataplexy. In order to further delineate the respective roles of the dopaminergic and noradrenergic systems in the pharmacological control of symptoms of narcolepsy, we compared the potency of amphetamine isomers (D- and L-amphetamines) and a derivative (L-methamphetamine) on wakefulness and cataplexy. Their respective effects on these narcolepsy symptoms were then compared with their in vivo effects on extracellular DA levels in the caudate and NE levels in the frontal cortex during local drug perfusion in narcoleptic dogs. Polygraphic recordings demonstrated that D-amphetamine was about twice as potent as L-amphetamine, and was six times more potent than L-methamphetamine in increasing wakefulness and reducing slow-wave sleep. D-Amphetamine and L-amphetamine were equipotent in reducing rapid eye movement sleep and cataplexy, and L-methamphetamine was about half as potent as L- and D-amphetamines. D-Amphetamine was found to be more potent in increasing DA efflux than L-amphetamine, and L-methamphetamine was found to have little effect on DA efflux; there was no significant difference in the potencies of the three derivatives on NE efflux. The potencies of these amphetamines on wakefulness correlated well with DA, but not NE, efflux in the brain of narcoleptic dogs during local drug perfusion. Our current results further exemplify the importance of the DA system for the pharmacological control of electroencephalogram arousal and suggest that increased DA transmission mediates the wake-promoting effects of amphetamine-like stimulants.

Thalidomide increases both REM and stage 3-4 sleep in human adults: a preliminary study.

Polysomnography was used to assess the effect of thalidomide on human sleep. This compound significantly increased the time spent in REM and stage 3-4 sleep as compared with placebo. On the other hand, thalidomide significantly decreased the time spent in stage 1, while the time spent in stage 2 was unchanged. The effect of thalidomide on REM and stage 3-4 sleep is unique as compared with other hypnotics. Although the mode of action of this compound is unknown, further studies on thalidomide should help in our understanding of the mechanisms of sleep regulation.

Sleep-disordered breathing in a patient with congenital myopathy.

A case of adult onset myopathy who showed a peculiar sleep-related respiratory disorder (SRRD) is reported. She recovered from respiratory failure after tracheostomy and/or with the aid of the respirator used only during the night. Sleep study without the use of respirator revealed that her sleep was highly fragmented by frequent arousal responses due to inspiratory effort but not by apnea or hypopnea. To our knowledge this type of SRRD has not been described.

Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy.

The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 microg/kg, i.v.) and TA0910 (100 and 400 microg/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 microg/kg, i.v.) had no significant effect. TRH (25-1600 microg/kg, i.v.) and all three TRH analogs, CG3703 (6. 25-400 microg/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 microg/kg, i.v.), and TA0910 (25-1600 microg/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T3 and T4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.