Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system

Summary

Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy–cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602).

The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS.

Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of 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. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures.

CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases.

Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

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.