Clinical ReviewSymptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system
Introduction
Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals.1, 2, 3 The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations (i.e. narcolepsy tetrad) as well as disturbed nighttime sleep (i.e. narcolepsy pentad).1 The disease was first described in medical literature at the end of the 19th century,4, 5 but the major pathophysiological mechanism of the disease was only revealed at the very end of the 20th century.
In 1999, using forward (i.e. positional cloning in familial narcolepsy in Dobermans/Labradors) and reverse genetics (i.e. mouse gene knockout), genes (i.e. prepro-hypocretin/-orexin and hypocretin/orexin receptor genes) involved in the pathogenesis of narcolepsy in animals were identified.6, 7 Mutations in the hypocretin-related genes (i.e. preprohypocretin gene) has been identified in a single early-onset case of narcolepsy–cataplexy.8 However, through cerebrospinal fluid (CSF) hypocretin-1 measures, it was found that a large majority of ‘idiopathic’ human narcolepsy cataplexy cases are associated with hypocretin ligand deficiency.9, 10, 11, 12, 13, 14, 15, 16 Postmortem studies in a small number of narcolepsy–cataplexy subjects confirmed the absence of hypocretin production in the brain parenchyma.8, 17 Soon after, it was also found that hypocretin ligand production (both in the CSF and brain) was not altered in narcoleptic Dobermans18 but instead the disease was caused by a mutation of hypocretin receptor 2,7 while hypocretin ligand deficiency was found in sporadic (non-familial) cases of narcoleptic dogs (seven out of seven cases tested, four cases are reported in Ref. 18). This suggests that the pathophysiology of sporadic narcoleptic dogs mirror those of most idiopathic cases of human narcolepsy.
Hypocretin (orexin) neurons are specifically localized in the lateral hypothalamus (LHA), but have widespread excitatory projections to monoaminergic, cholinergic and GABAergic neurons in brainstem, basal forebrain, cortex and spinal cord.19, 20, 21 Hypocretin neurons in turn, receive inputs from excitatory (glutamatergic) and inhibitory (noradrenergic, serotonergic and GABA-ergic) neurons.22 Hypocretin neurons are thought to be implicated in maintaining wakefulness and regulating motor functions (locomotion, muscle tone), feeding, energy expenditure and sympathetic activity.21, 23 Hypocretin systems may thus play a key role in orchestrating various fundamental hypothalamic functions that are linked with ‘ergotropic’ behavioral states.
Since hypocretin deficiency in narcolepsy is also tightly associated with the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602),12, 13 an acquired cell loss of hypocretin containing neurons with autoimmune process is suggested in ‘so-called’ idiopathic cases of narcolepsy. ‘Idiopathic narcolepsy’ has been used for the cases with narcolepsy unassociated with apparent radiographical or clinical evidence of brain pathology apart from sleep-related abnormalities. Normal CSF hypocretin-1 levels are above 200 pg/ml regardless of gender, age (from neonatal to 70s) and time of the CSF collections.10, 12 In contrast to hypocretin-1, hypocretin-2 is very unstable and not measurable in the CSF,24 but both hypocretin-1 and -2 were found to be significantly reduced in the postmortem narcoleptic brains.12 In the direct assays (without extraction) done both at Stanford University and other facilities performing a compatible method, CSF hypocretin levels are defined as low (<110 pg/ml), intermediate (110–200 pg/ml) and normal (>200 pg/ml). Since the specificity and sensitivity of low CSF hypocretin-1 level (30% of the normal levels) for narcolepsy–cataplexy is high among various sleep disorders,13, 25 low CSF hypocretin-1 level will be included in the second revision of the International classification of Sleep Disorders (ICSD) for narcolepsy–cataplexy.
Impaired hypocretin systems may also be observed in some neurological disorders affecting the LHA (where hypocretin cell bodies locate) and hypocretin projection pathways. Indeed, an earlier study by Ripley et al., reported CSF hypocretin levels in 235 neurological patients and found that a subset of subjects with acute or sub-acute neurological disorders had decreased CSF hypocretin levels.26 Interestingly, CSF hypocretin-1 levels in the majority of patients with chronic neurologic conditions (such as Alzheimer's disease and Parkinson disease) are not significantly reduced. The neurological conditions in which a subset had reduced CSF hypocretin levels include intracranial tumors, cerebrovascular events, craniocerebral trauma, CNS infections and Guillain-Barré Syndrome (GBS) (Fig. 1).26 Arii et al.27 recently studied CSF hypocretin levels in 132 pediatric neurological conditions, and the results are consistent with Ripley's study,26 where only a limited number of neurological conditions besides narcolepsy–cataplexy showed reduced CSF hypocretin-1 levels.27 These include intracranial tumors, craniocerebral trauma and autoimmune and postinfectious disease (GBS and acute disseminated encephalomyelitis, ADEM) as well as several inherited diseases (Table 1).
These findings are particularly interesting since these acute and sub-acute neurological conditions are often associated with disturbed consciousness, lethargy, sleepiness, and/or residual sleep disturbances. Association with EDS/cataplexy in some inherited diseases (such as Niemann-Pick disease, type C (NPC), Prader-Willi syndrome (PWS) myotonic dystrophy) is also known.28, 29, 30 An impaired hypocretin system may also be involved in some sleep-related symptoms in conjunction with these neurological conditions.
In rare cases, symptoms of narcolepsy can be seen during the course of a neurological disease process (i.e. symptomatic narcolepsy). Several authors31, 32, 33, 34, 35, 36, 37, 38, 39 have previously reviewed the details of these cases. Interestingly, involvements of the hypothalamic structures in these symptomatic narcoleptic cases are emphasized repeatedly from several decades ago,40, 41 and thus, an impaired hypocretin system may also be directly involved in some of these symptomatic cases of narcolepsy.
In this review, we will initially look at cases with symptomatic narcolepsy as well as rare cases of symptomatic cataplexy (i.e. isolated cataplexy) in the literature (Fig. 2 and Appendix).
Along with the progress in the understanding of the pathophysiological mechanisms of idiopathic narcolepsy (i.e. hypocretin deficiency), several new neuroimaging technologies have also become available. In the second part of the review, we will present high-resolution T1 and/or T2-weighted magnetic resonance imaging (MRI) findings together with the results of CSF hypocretin-1 measures in various symptomatic narcolepsy cases, and discuss the functional and anatomical involvements of the hyprocretin system in these cases (Table 2 and Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9). Since hypersomnia without other narcolepsy symptoms can also occur with a variety of neurological disorders that are not related to narcolepsy, we will also extend our review on roles of the hypocretin system in hypersomnia associated with various neurological conditions. We use ‘hypersomnia’ and ‘EDS’ synonymously in this review as described by “the inability to stay alert and awake during the major waking episodes of the day, resulting in unintended lapses into sleep”. Sleepiness may vary in severity and is more likely to occur in boring, monotonous situations that require no active participation. In some cases, sleepiness is associated with large increases in total daily amount of sleep without any genuine feeling of restoration. In other cases, sleepiness is not associated with increases in the total daily amount of sleep. Sleepiness can be alleviated temporarily by naps, but recurs as typically seen in most idiopathic cases of narcolepsy.
Based on frequency and nosological considerations, we categorized the cases as follows: (1) symptomatic narcolepsy–cataplexy associated with focal/generalized central nervous system (CNS) invasion, such as cerebral tumors, vascular diseases, and neurodegenerative disorders, (2) symptomatic cataplexy with (2a) focal/generalized central nervous system (CNS) invasion and (2b) cataplexy-like attacks in inherited/congenital disorders and (3) hypersomnia associated with (3a) focal/generalized CNS invasion, such as cerebral tumors, brain infections, vascular diseases, head trauma and neurodegenerative disorders (Alzheimer's disease, Parkinson's disease), and (3b) with CNS diseases mediated with neuroimmune mechanisms, such as inflammatory and demyelinating diseases. The latter hypersomnia categories (3a, b) likely consist of heterogeneous conditions and include less defined hypersomnia cases. This is partially due to the fact that applying standardized polygraphic assessments (all night polygraphic recordings followed by MSLT) was sometimes difficult in many of these neurological conditions. However, since prevalence of these hypersomnia/EDS cases appeared to be much higher than that of symptomatic narcolepsy, the discussion on these cases is likely to have clinical implications.
Section snippets
Definition of symptomatic narcolepsy
Symptoms of narcolepsy can sometimes be seen during the course of a neurological disease process. In such instances, the term ‘symptomatic narcolepsy’ is used, implying that narcolepsy is a symptom of the underlying process rather than idiopathic. In this case, the signs and symptoms of narcolepsy should be temporally associated with the underlying neurological process. Symptomatic narcolepsy and ‘secondary narcolepsy’ are used more or less indiscriminately, even though they apparently have
Overview of symptomatic narcolepsy cases reported
Using our criteria, we have counted 116 symptomatic cases of narcolepsy reported in literature (Fig. 2a) (the demographic and clinical data are reported in the table in Appendix). As reported previously by several authors, inherited disorders, tumors, and head trauma are the three most frequent causes for symptomatic narcolepsy. Ten cases are associated with multiple sclerosis (MS), one case of ADEM, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and
Anatomical substrate for the symptoms of narcolepsy
Von Economo85 was probably the first person to suggest that narcolepsy may have its origins in the posterior hypothalamus and in some cases, a secondary etiology. Neuropathological studies on encephalitis lethargica pandemic (1916–1923) revealed involvements of the midbrain periaqueducal gray matter and posterior hypothalamus in the hypersomnolent variant, with frequent extensions to the oculomotor nuclei. This led von Economo to speculate that the anterior hypothalamus contained a
Symptomatic cataplexy associated with focal/generalized CNS invasion
Ethelberg102 had reported two cases of cataplexy-like attacks associated with head trauma. Two subjects (a 25-year-old male and a 14-year-old female) had depressed fractures, making impressions on the lateral surface of the frontal lobe corresponding to the anterior part of the motor cortex. Supposed cataplexy or attacks of general limpness developed in both cases, sometimes associated with blunting or loss of consciousness and emotional provocation of these attacks, was not seen in both cases.
General considerations of CSF hypocretin-1 measures
Although CSF hypocretin-1 was measured in extracted CSF samples (using a sep-pack C18 reversed phase column) in the initial sets of experiments,9, 10 we also found that CSF hypocretin-1 levels can be reliably measured by the direct assay (in 100 μl) without any extraction. Indeed, measured CSF hypocretin-1 values correlated well with those measured with the sep-pack extraction in healthy subjects and in various neurological conditions.26 Hypocretin-1 signals in the CSF were very stable, and the
Focal/generalized CNS invasion
Symptomatic narcolepsy is relatively rare, but sleepiness without other narcoleptic symptoms can often occur with a variety of neurological disorders; they are more likely to be due to multifocal or global disturbances of the brainstem, diencephalon and cerebral cortex. Recently, several clinical studies also suggested that the disruption of the hypothalamic hypocretin system in EDS is associated with various neurological conditions.
Conclusion
Symptoms of narcolepsy can occur during the course of neurological conditions. Although it is difficult to rule out the comorbility of idiopathic narcolepsy in some cases, the review of literature reveals numerous unquestionable cases with symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease.
Symptomatic cases of narcolepsy are most often
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