Low cerebrospinal fluid hypocretin levels found in familial narcolepsy

OBJECTIVE: This report describes abnormal hypocretin neurotransmission in a case of familial narcolepsy. BACKGROUND: Narcolepsy is a chronic, often-disabling central nervous system disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep features including cataplexy, a loss of muscle tone triggered by emotion. The cause of human narcolepsy is unknown. Several familial cases have been described, but most cases are sporadic (95%). An abnormality of hypocretin neurotransmission has been found in a majority of sporadic cases. METHODS: Hypocretin-1 levels were measured in the cerebrospinal fluid of the narcoleptic proband of a family with several affected members. RESULTS: The proband was found to have a hypocretin-1 deficiency. CONCLUSION: Abnormal hypocretin neurotransmission is found in familial, as well as sporadic, narcolepsy.     

Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy

Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal models. In humans, narcolepsy is rarely due to hypocretin mutations, but this system is deficient in the cerebrospinal fluid (CSF) and brain of a small number of patients. A recent study also indicates increased body mass index (BMI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQB1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was measurable (169 to 376 pg/ml) in all controls. Levels were unaffected by freezing/thawing or prolonged storage and did not display any concentration gradient. Hypocretin-1 was dramatically decreased (<100 pg/ml) in 32 of 38 patients (all HLA-positive). Four patients had normal levels (2 HLA-negative). Two HLA-positive patients had high levels (609 and 637 pg/ml). CSF leptin and adjusted BMI were significantly higher in patients versus controls. We conclude that the hypocretin ligand is deficient in most cases of human narcolepsy, providing possible diagnostic applications. Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system.     

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 microL 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.     

CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions

OBJECTIVE: To determine the role of CSF hypocretin-1 in narcolepsy with and without cataplexy, Kleine-Levin syndrome (KLS), idiopathic and other hypersomnias, and several neurological conditions. PATIENTS: 26 narcoleptic patients with cataplexy, 9 narcoleptic patients without cataplexy, 2 patients with abnormal REM-sleep-associated hypersomnia, 7 patients with idiopathic hypersomnia, 2 patients with post-traumatic hypersomnia, 4 patients with KLS, and 88 patients with other neurological disorders. RESULTS: 23 patients with narcolepsy-cataplexy had low CSF hypocretin-1 levels, while one patient had a normal hypocretin level (HLA-DQB1*0602 negative) and the other two had intermediate levels (familial forms). One narcoleptic patient without cataplexy had a low hypocretin level. One patient affected with post-traumatic hypersomnia had intermediate hypocretin levels. The KLS patients had normal hypocretin levels while asymptomatic, but one KLS patient (also affected with Prader-Willi syndrome) showed a twofold decrease in hypocretin levels during a symptomatic episode. Among the patients without hypersomnia, two patients with normal pressure hydrocephalus and one with unclear central vertigo had intermediate levels. CONCLUSION: Low CSF hypocretin-1 is highly specific (99.1%) and sensitive (88.5%) for narcolepsy with cataplexy. Hypocretin ligand deficiency appears not to be the major cause for other hypersomnias, with a possible continuum in the pathophysiology of narcolepsy without cataplexy and idiopathic hypersomnia. However, partial hypocretin lesions without low CSF hypocretin-1 consequences cannot be definitely excluded in those disorders. The existence of normal hypocretin levels in narcoleptic patients and intermediate levels in other rare aetiologies needs further investigation, especially for KLS, to establish the functional significance of hypocretin neurotransmission alterations.     

The value of the measurement of cerebrospinal fluid levels of lysozyme in the diagnosis of neurological disease.

A turbidimetric technique has been adapted to yield maximum sensitivity for the measurement of lysozyme in cerebrospinal fluid. One hundred and ninety-eight patients were studied over a total period of 9 months using this technique. In addition to the considerably elevated levels known to occur in cases of bacterial and fungal meningitis, increased activity was also demonstrated in cases of subarachnoid haemorrhage and in certain inflammatory conditions. Normal or marginally increased levels were seen in cases of viral meningitis and encephalitis.     

Increased cerebrospinal fluid levels of nerve cell biomarkers in narcolepsy with cataplexy

BackgroundThe association between narcolepsy with cataplexy and the hypocretinergic system in the central nervous system is strong since up to 75–90% of all patients have cerebrospinal fluid (CSF) hypocretin-1 deficiency. The predominant occurrence of HLADQB1*0602 tissue type in narcolepsy patients and recent results from genome-wide association studies suggest an underlying immunological mechanism. The present study was initiated to clarify whether measurement of nerve cell biomarkers in CSF could give additional knowledge of the pathophysiological mechanisms causing narcolepsy with cataplexy.MethodsTwo patient groups with narcolepsy, comprising 18 patients with low CSF hypocretin-1 concentrations and typical cataplexy, and 18 patients with normal CSF hypocretin-1 levels and mild cataplexy-like symptoms, were compared to 17 controls. We measured the nerve cell biomarkers beta-amyloid (Aβ₄₂), total tau protein (T-tau), phosphorylated tau (P-tau) and neuron-specific enolase (NSE) in CSF.ResultsThe concentrations of all biomarkers were significantly elevated in both patient groups compared to the controls. The concentration of beta-amyloid was significantly higher in the patient group with normal CSF hypocretin-1 concentration than in those with low concentrations, whereas the other biomarkers showed no difference between the patient groups.ConclusionThe findings of elevated levels of CSF biomarkers independent of CSF hypocretin-1 reduction may reflect alterations in cell metabolism. The results suggest a more extensive affection of the sleep regulating cellular network, affecting other neuronal sites important in the regulation of sleep, in addition to the hypocretin-producing neurons.     

Polymorphisms in hypocretin/orexin pathway genes and narcolepsy.

The neuroexcitatory peptide hypocretin and its receptors are central to the pathophysiology of both human and animal models of the disease. In this study of American and Icelandic patients with narcolepsy, the authors found no significant association between narcolepsy and single-nucleotide polymorphisms in the genes for hypocretin or its two known receptors, hypocretin receptor-1 and hypocretin receptor-2.     

Elevated glial fibrillary acidic protein levels in the cerebrospinal fluid of patients with narcolepsy

Glial fibrillary acidic protein (GFAP) is an established indicator of astrogliosis. Therefore, variable cerebrospinal fluid (CSF) concentrations of this protein might reflect disease-specific pathologic profiles. In patients with narcolepsy, a loss of hypocretin-1 (hcrt-1) neurons in the brain and low concentrations of hcrt-1 in CSF have been reported. We performed a commercially available enzyme-linked immunosorbent assay to investigate if GFAP also is altered in the CSF of these patients. Here we detected significantly higher CSF levels of GFAP in patients with low hcrt-1 levels, of which the majority had a diagnosis of narcolepsy and cataplexy (NC); however, this finding was not observed in patients with hcrt-1 levels that were within reference range. In conclusion, GFAP may be useful as an additional disease biomarker in patients with narcolepsy, and this hypothesis should be investigated in larger studies.     

The possible role of cerebrospinal fluid adenosine deaminase activity in the diagnosis of tuberculous meningitis in adults.

We studied an adenosine deaminase (ADA) activity in the cerebrospinal fluid (CSF) of 182 patients with meningitis. The patients were subdivided into four groups, (1) 36 cases of tuberculous meningitis; (2) 130 cases of viral or aseptic meningitis; (3) nine cases of bacterial meningitis; (4) seven cases of cryptococcal meningitis. Mean+/-S.D. ADA activity was 12.76+/-7.53 U/l in group 1; 2.58+/-2.37 U/l in group 2; 7.38+/-3.27 U/l in group 3; 7.42+/-4.38 U/l in group 4. Comparing the ADA activity in each group with the other groups, the difference is significant (P<0.001), except between groups 3 and 4. The sensitivity of the test for group 1 compared with group 2 was 0.83 and the specificity was 0.95 when a cut-off value of 7 U/l was used. When group 1 was compared with groups 3 and 4, the sensitivity was 0.58 and the specificity was 0.89 and 0.71 with groups 3 and 4, respectively, when a cut-off value of 10 U/l was used. Values >15 U/l were not observed in any of the non-tuberculous meningitis patients; therefore, ADA activity >15 U/l could be a strong indication of tuberculous meningitis. We conclude that a determination of CSF ADA can aid in the early differential diagnosis of tuberculous meningitis.     

A case of acute disseminated encephalomyelitis presenting hypersomnia with decreased hypocretin level in cerebrospinal fluid

A 12-year-old girl was diagnosed as having acute disseminated encephalomyelitis and manifested hypersomnia as the main clinical feature. Magnetic resonance imaging (MRI) revealed lesions in the bilateral hypothalamus in addition to other multifocal brain lesions involving the cerebral white matter, brain stem, and basal ganglia. The level of hypocretin in cerebrospinal fluid was decreased in this patient. Corticosteroid treatment resulted in improvement of the hypersomnia and resolution of MRI lesions in the hypothalamus and other regions. This case suggests that the arousal state control mechanism related to the hypocretin peptide/receptor system may be impaired in some patients with acute disseminated encephalomyelitis.     

Use of chromogenic substrate in cerebrospinal fluid diagnosis

Amidolytic assays with chromogenic substrates exhibit great sensitivity, easy management, and good reproducibility. Consequently, they can be used with advantage in the analysis of cerebrospinal fluid (CSF). CSF levels of alpha 2-macroglobulin, alpha 1-antitrypsin, and plasminogen can thus be determined without a concentration step prior to analysis--lowered alpha 1-antitrypsin levels included. Serum/CSF concentration ratios obtained with these assays agree well with data calculated from immunochemical procedures. Moreover, there was a good correlation between amidolytic and immunochemical procedures. These reflections make it apparent that they can be adapted for routine evaluation of the above mentioned parameters.     

Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis

The diagnosis of leptomeningeal metastasis is often difficult and usually requires the demonstration of malignant cells in the cerebrospinal fluid. Neuroimaging, however, may establish or support the diagnosis in some patients. Radiographic abnormalities consistent with or suggestive of leptomeningeal metastasis include leptomeningeal, subependymal, dural, or cranial nerve enhancement; superficial cerebral lesions; and communicating hydrocephalus. We evaluated 137 cancer patients with clinical symptoms suspicious for leptomeningeal metastasis with neuroimaging or cerebrospinal fluid cytology or both. Neuroimaging findings were abnormal in 70 of 128 tested patients; cytology was performed in 58 of these 70 and the results were positive in 37. Conversely, cytological findings were positive in 53 of 115 tested patients; neuroimaging was performed in 49 of these 53 and the findings were abnormal in 37 (26/29 solid tumors and 11/20 hematological tumors). Of the total series of 137 patients, leptomeningeal metastasis was diagnosed in 77; in 24 (31%) the diagnosis was made on the basis of clinical picture and abnormal neuroimaging alone. Neuroimaging is a valuable tool in the investigation of leptomeningeal metastasis in the cancer population, and the presence of typical clinical features together with appropriate neuroimaging abnormalities is adequate to make the diagnosis of leptomeningeal metastasis even if cerebrospinal fluid cytological results are negative.