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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 39  |  Issue : 4  |  Page : 165-176

Neuroanatomical and Etiological Approaches to Secondary Narcolepsy


Department of Neurology, Sleep and Disorders Unit, Cerrahpasa Faculty of Medicine, Istanbul University, Cerrahpasa, Istanbul, Turkey

Date of Submission10-Jan-2022
Date of Decision29-May-2022
Date of Acceptance31-May-2022
Date of Web Publication19-Dec-2022

Correspondence Address:
Gulcin Benbir Senel
Department of Neurology, Sleep and Disorders Unit, Cerrahpasa Faculty of Medicine, Istanbul University, Cerrahpasa, Istanbul, 34098
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/nsn.nsn_5_22

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  Abstract 


Narcolepsy is one among the disorders of central hypersomnolence characterized by excessive daytime sleepiness not related to disturbances in nocturnal sleep or misalignment in circadian rhythms. The cardinal symptom of this group of disorders is disabling daytime sleepiness, characterized by the repeated episodes of irresistible daytime sleepiness or lapses into sleep in monotonous situations, but also under unusual conditions such as eating. Narcolepsy is defined as type 1 and type 2 on the basis of the presence of cataplexy. The most pathognomonic feature of narcolepsy type 1 is cataplexy, which is characterized by sudden episodes of brief loss of muscle tone-sparing consciousness, usually triggered by strong emotions. Other nonspecific symptoms associated with rapid eye movement sleep dissociation include fragmentation of nocturnal sleep, hypnagogic or hypnopompic hallucinations, and sleep paralysis. The pathophysiology of narcolepsy type 1 is well established as the deficiency of hypocretin (orexin) signaling in the lateral hypothalamus. In narcolepsy type 2, on the other hand, hypocretin levels are not decreased, and it has been suggested that there is probably a partial deficiency in hypocretin signaling system to cause excessive daytime sleepiness but not severe enough to cause cataplexy. Instead of types 1 and 2, primary (idiopathic) narcolepsy, familial narcolepsy, secondary (symptomatic) narcolepsy, and narcolepsy plus (hereditary forms with additional neurological symptoms) forms were suggested to better classify the clinical entities. In this paper, the diagnosis of symptomatic or secondary narcolepsy is reviewed and classified based on the underlying pathophysiologic mechanisms.

Keywords: Narcolepsy, pathophysiology, secondary narcolepsy


How to cite this article:
Senel GB, Karadeniz D. Neuroanatomical and Etiological Approaches to Secondary Narcolepsy. Neurol Sci Neurophysiol 2022;39:165-76

How to cite this URL:
Senel GB, Karadeniz D. Neuroanatomical and Etiological Approaches to Secondary Narcolepsy. Neurol Sci Neurophysiol [serial online] 2022 [cited 2023 Feb 5];39:165-76. Available from: http://www.nsnjournal.org/text.asp?2022/39/4/165/364422




  Introduction Top


The first descriptions of narcolepsy were reported by Westphal and Gelineau, who described patients with irresistible sleep attacks without any apparent cause and sudden falls on emotion with muscle relaxation.[1] Although different names have been used in the literature, the term “narcolepsy” for the sleep attacks and the term “cataplexy” for the loss of muscle tone were first proposed by Adie. In addition to his clinical contributions, Adie has suggested that narcolepsy was an “endocrine–nervous” disorder in origin. With the reference to von Economo's encephalitis lethargica, he further defined “the floor of the tween brain and the pituitary system” as the crucial region for narcolepsy. On the other hand, his senior colleague Wilson argued with the full definitions by Adie but reported that both idiopathic and secondary causes of narcolepsy existed, as he gave examples of several causes, including traumatic, endocrine, epileptic, toxi-infective, circulatory, and tumor-related narcolepsy. In addition, he also described that narcolepsy or cataplexy may exist in isolation without accompanying each other, or cataplexy may occur without any emotional trigger. Although Wilson agreed with Adie in the presence of a common factor underlying all clinical phenomena, he concluded that narcolepsy was not a single disorder and has not fully understood. Although Adie and Wilson were unable to predict the hypothalamus and a peptide produced from this region, namely hypocretin, in the pathophysiology of narcolepsy and cataplexy, their definitions and hypotheses on the topography and etiology have anticipated the current understanding of this intriguing disease.

Narcolepsy is one among the disorders of central hypersomnolence characterized by excessive daytime sleepiness not related to disturbances in nocturnal sleep or misalignment in circadian rhythms.[2] The cardinal symptom of this group of disorders is disabling daytime sleepiness, characterized by the repeated episodes of irresistible daytime sleepiness or lapses into sleep in monotonous situations, but also under unusual conditions such as eating. Mostly, patients awaken very refreshed following a daytime nap, though they have lapses in vigilance or feel very sleepy again repeatedly many times during the day. Narcolepsy is defined as type 1 and type 2 on the basis of the presence of cataplexy. The most pathognomonic feature of narcolepsy type 1 is cataplexy, which is characterized by sudden episodes of brief loss of muscle tone-sparing consciousness, usually triggered by strong emotions. Other nonspecific symptoms associated with rapid eye movement (REM) sleep dissociation include fragmentation of nocturnal sleep, hypnagogic or hypnopompic hallucinations, and sleep paralysis.[3]


  Diagnostic Issues Top


The pathophysiology of narcolepsy type 1 is well established as the deficiency of hypocretin (orexin) signaling in the lateral hypothalamus.[4] In narcolepsy type 2, on the other hand, hypocretin levels are not decreased, while postmortem studies have revealed a decrease in hypocretinergic neurons in the hypothalamus. It has been suggested that there is probably a partial deficiency in hypocretin signaling system to cause excessive daytime sleepiness but not severe enough to cause cataplexy. The current diagnostic criteria for narcolepsy have mainly based on the findings of multiple sleep latency test (MSLT) in the absence of hypocretin measurement.[5],[6] A revision in diagnostic criteria for narcolepsy has recently been proposed.[5] Instead of types 1 and 2, primary (idiopathic) narcolepsy, familial narcolepsy, secondary (symptomatic) narcolepsy, and narcolepsy plus (hereditary forms with additional neurological symptoms) forms were suggested to better classify the clinical entities. Definitions including “hypersomnia due to medical disorder,” “hypersomnia due to substance abuse,” or “hypersomnia associated with a psychiatric disorder” were not suggested any more mainly because it is difficult to define precisely whether the relationship was causal or comorbidity. According to this proposal, the diagnosis of symptomatic or secondary narcolepsy needs the presence of excessive daytime sleepiness with cataplexy or cataplexy-like episodes, and the patients should have Niemann-Pick type C, Prader-Willi syndrome, or a lesion in the hypothalamus. A typical MSLT feature or hypocretin deficiency should also be present.[5]


  Pathophysiology of Primary (”Idiopathic”) Narcolepsy Top


It is now known that narcolepsy type 1 is strongly associated with a dysfunction in the hypocretinergic signaling system. In one report, on the other hand, concordant narcolepsy type 1 was identified in monozygotic twins, in whom hypocretin levels in the cerebrospinal fluid (CSF) were normal and no mutation was present in hypocretin or receptor genes.[7] Likewise, in narcolepsy type 2, a similar clinical phenomenology with narcolepsy type 1 is observed in spite of normal hypocretinergic signaling system. These data support the hypothesis that hypocretinergic dysfunction may not be the only affected pathway in the pathophysiology of narcolepsy. The question whether the lack of hypocretin deficiency represents a different clinical entity related to another arousal systems waits to be answered. Secondary narcolepsy, such as resulting from tumors or trauma, may also constitute some of these presentations.

The latest hypothesis unites multiple factors in the etiopathogenesis of narcolepsy as the coexistence of genetic predisposition and triggering environmental factors, which eventually result in selective dysfunction of hypocretin-producing neurons in the hypothalamus, possibly via immune-mediated destruction.[3] In humans, although reductions in hypocretin (lower than 110 pg/ml) and pre-pro-hypocretin mRNA levels were well documented, all studies have failed to found mutations except for one study,[8] in which Peyron et al. have found a mutation in the Hcrt gene itself. The direct evidence of narcolepsy-specific antibodies is also not present, while narcolepsy is closely linked to distinct human leukocyte antigen (HLA) DQB1*06:02 haplotype (in 90%–100% of type 1 and 40% of type 2) and associated with the region of HLA class II-encoding antigenic peptides to T cells.[3],[9],[10]


  Etiology of Secondary (”Symptomatic”) Narcolepsy Top


Although hypocretin deficiency is the main pathophysiologic substrate for narcolepsy type 1, narcolepsy may be seen also in the absence of hypocretin deficiency. On the other hand, hypocretin deficiency is not accepted as the equivalent of narcolepsy. While this equation may be true to some extent, the underlying etiology leading to hypocretin deficiency constitutes the main difference between narcolepsy and the other clinical forms associated with hypocretin deficiency. There are controversial concepts on the nosology of secondary or symptomatic narcolepsy. Nishino and Kanbayashi[11] have stated that “symptomatic” and “secondary” narcolepsy had different meanings, for which they suggested the use of symptomatic narcolepsy/excessive daytime sleepiness (EDS) in the presence of an underlying neurological disorder being responsible for the EDS with temporal association. Bassetti et al.,[3] on the other hand, have brought an etiological approach and classified narcolepsy in four groups; as (i) sporadic idiopathic narcolepsy, (ii) familial narcolepsy, (iii) sporadic secondary narcolepsy, and (iv) hereditary secondary narcolepsy (”narcolepsy-plus” syndromes).

The current diagnostic criteria of narcolepsy have many drawbacks and been criticized to require revisions. The current international classification does not provide a validated definition for cataplexy and different phenotypes. Because a biomarker is missing for the diagnosis of cataplexy, the diagnosis is only based on clinical history, and the experiences of the patients may not always be accurate. Cataplexy is a pathognomonic clinical feature in narcolepsy type 1; however, it may not be present at the same time with the excessive daytime sleepiness but evolve after months or also after years. A clear identification of cataplexy or the use of a diagnostic tool is therefore crucial. MSLT findings, as defined among the diagnostic criteria, may also be found in 15% of the patients with otherwise typical narcolepsy, and the value of nonspecific sleep-onset REM periods (SOREMPs) is being overemphasized.[3],[4] The measurement of CSF hypocretin has methodological issues, and HLADQB1*06:02 positivity is even not included in the current criteria. It seems that the classification of narcolepsy will be renewed to present better diagnostic tools for primary or idiopathic narcolepsy and to embrace different clinical and etiological phenotypes.

One may assume that it would be difficult to differentiate between comorbidity in a patient with primary (idiopathic) narcolepsy and symptomatic narcolepsy, in addition to unquestionable conditions. Atypical characteristics of narcolepsy may give some clues for the secondary cases, such as late age at disease onset, close temporal relationship with the comorbid disease, and HLA negativity. In clinical evaluation, the majority of cases were interestingly reported to present with excessive daytime sleepiness, while cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis were only rarely associated.[12] Evaluation of clinical cases in regard to underlying etiology, very heterogeneous groups have emerged with no remarkable clinicopathologic correlation. In this regard, although symptomatic cases of narcolepsy do exist, some of the reported cases in the literature may likely to represent “narcolepsy-like” syndromes with variable combinations of excessive daytime sleepiness, cataplexy or cataplexy-like attacks, short sleep latency or SOREMPs, or low hypocretin levels, which do not fulfill the revised diagnostic criteria of narcolepsy.[5]

Neuroanatomic basis of narcolepsy is mainly the hypocretinergic system located in the laterodorsal hypothalamus, while target neuronal groups located in the mesencephalon, pons, and medulla oblongata may also be responsible, at least in part, in the emergence of symptoms related with narcolepsy [Figure 1]. Direct structural damages or autoimmune processes affecting these brain regions may lead to disturbances in hypocretinergic signaling system. In a meta-analysis of symptomatic narcolepsies, the most common localization was demonstrated as hypothalamus for the excessive daytime sleepiness, while nonhypothalamic localizations were more frequently associated with symptomatic cataplexy.[11] Among underlying etiology, almost one-third of the cases were related to inherited disorders, followed by tumoral lesions. The measurements of CSF hypocretin levels were not performed in many of the studies, and some underlying etiologies were not necessarily linked to dysfunction in hypocretinergic signaling system. One may expect an association of narcolepsy with the lesions in the hypothalamus and nearby regions; demyelinating lesions, tumors, or cerebrovascular events were commonly reported to involve these brain structures. In this term, congenital disorders such as Prader-Willi syndrome or Niemann-Pick disease type C, or traumatic lesions of the hypothalamus may be accepted as symptomatic or secondary narcolepsy.[5],[13] On the other side, monoamine neurons located in the locus coeruleus, raphe nucleus, tuberomammillary nucleus, and ventral tegmental area are also linked to hypocretinergic systems. Although hypocretinergic deficiency leads to dysfunction in these monoaminergic systems, abnormalities in the adrenergic and serotonergic systems may also lead to disturbances in maintaining wakefulness and REM-sleep–related abnormalities, mimicking narcolepsy and leading the emergence of “narcolepsy-like” syndromes.[14]
Figure 1: Neuroanatomic basis of the hypocretinergic system. (BF, Basal forebrain; ACh, Acetylcholine; PPT, Pedunculopontine tegmentum; LDT, Laterodorsal tegmentum; TMN, Tuberomammillary nucleus; HA, Histamine; SN, Substantia nigra; VTA, Ventral tegmental area; DA, Dopamine; 5-HT, 5-hydroxytryptamine; LC, Locus coeruleus; NE, Norepinephrine)

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In this review, we summarized and categorized the symptomatic or secondary narcolepsy on the basis of neuroanatomic and etiologic basis. In neuroanatomic approach, diseases or conditions related with narcolepsy were covered under two titles as “Hypothalamic involvement” and “Involvement of other brain regions.” Neuroanatomic involvement was further subdivided into two according to the pathophysiologic mechanisms. In pathophysiologic basis, etiologies were separated into two as being related to a “Structural pathology” or an “Autoimmune process” [Table 1].
Table 1: Neuroanatomic and etiologic classification of symptomatic (secondary) narcolepsy and “narcolepsy-like” conditions

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Hypothalamic involvement

Hypoconnectivity between hypothalamus and its either direct or indirect projections with hypocretinergic network including reticular formation, locus coeruleus, hippocampus, amygdala, and cortical regions such as frontal and temporal cortices has previously been identified in primary narcolepsy.[15] From etiological stand view, the most common causes of symptomatic or secondary narcolepsy are of structural pathologies, such as focal lesions in the hypothalamus such as tumors and cerebrovascular or demyelinating disorders. However, not all cases with hypocretin deficiency should be accepted as symptomatic or secondary narcolepsy but should carefully be handled in terms of clinical conditions mimicking narcolepsy, as mentioned above. In addition, nonstructural pathologies have also been linked to disturbances in hypocretinergic signaling system, possibly via autoimmune-based mechanisms [Table 1].

Structural pathologies

It is now well known that hypocretin-producing neurons located in the laterodorsal hypothalamus are the main anatomic localizations responsible for the development of narcolepsy. Any structural lesion affecting these neurons resulting in destruction may actually result in the emergence of symptomatic narcolepsy secondary to underlying etiology.

Tumors or granulomatous lesions

Although symptomatic or secondary narcolepsy is rare, it has mostly reported in association with tumoral lesions in the hypothalamic region.[12] Nevertheless, not all tumors located in the hypothalamic region cause excessive daytime sleepiness, and even less is associated with the presence of cataplexy. There are case reports presenting with narcolepsy-like daytime sleepiness in the literature, demonstrating different types of benign or malignant tumors, involving hypothalamic regions such as developmental tumors (i.e., craniopharyngiomas, or Rathke's tumor), neoplasms of primary central nervous system (i.e., hypothalamic astrocytomas), or metastatic tumors.

Craniopharyngiomas, classified as World Health Organization grade I malignant tumors, develop from ectoblastic remnants of Rathke's pouch and therefore are localized in the hypothalamic and pituitary regions along the path of development of Rathke's pouch. In pediatric age group, they are the most common intracranial tumors of nonglial origin (6%–9%), with a peak incidence at 5–10 years of age, which coincides with peak incidence of narcolepsy. Nevertheless, they may occur at any age starting from infancy to the sixth decade. First presenting symptoms include headache, impaired vision, and endocrine disturbances. In a review by Müller,[12] excessive daytime sleepiness was reported to be present in about one-third of the patients with childhood craniopharyngiomas. In a study evaluating polysomnography (PSG) and multiple sleep latency test (MSLT) findings in seven patients with craniopharyngiomas, only one patient was found to meet the criteria for narcolepsy type 2, while sleep and wake disturbances were more commonly present.[16] CSF hypocretin levels were reported to be normal. In a recent retrospective review, three patients with narcolepsy type 2 secondary to craniopharyngioma were reported, one of which showed a spontaneous remission of sleepiness.[17] A patient with Rathke's pouch tumor was reported by the authors,[18] in whom excessive daytime sleepiness was present since the age of 41 years and the diagnosis of narcolepsy type 2 was made on the basis of clinical and MSLT findings.

Among other malignancies, glioblastoma in the rostral brainstem and hypothalamus was linked to secondary narcolepsy with cataplexy.[19] In another case, a severe narcolepsy was reported in a patient with B-cell lymphoma due to widespread infiltrations in brain, in whom HLA DQB1*0602 was negative.[20] CSF hypocretin level was undetectable in this patient but reversed to be normal 8 months after treatment with chemotherapy.

Symptomatic or secondary narcolepsy associated with suprasellar and hypothalamic tumors was mainly hypothesized to result from damage or loss of hypothalamic hypocretin-containing neurons.[21] There are two case reports in the literature,[22],[23] in whom clinical symptomatology of narcolepsy and cataplexy appeared following the surgery for craniopharyngiomas. CSF hypocretin level was found below the cutoff value in either case, while in one case report,[22] HLA typing was also positive for DRB1*0101/0901-DQB1*0303/0501 alleles. Diffusion tensor magnetic resonance imaging (MRI) and fiber tractography were also performed in this case, which revealed the loss of connections from hypothalamus to frontal lobe. These findings were interpreted as secondary to the damage in hypothalamus due to surgery rather than the tumor itself.

In one case report,[24] development of narcolepsy at an unusual age was presented in a patient who received cranial radiation for astrocytoma at the left parietal lobe. The emergence of narcolepsy-related symptoms occurred at the peak time of late radiation effect. Although cranial neuroimaging did not show any lesion in the hypothalamus, the authors have suggested that this did not exclude a late radiation injury as the underlying mechanism may be chronic vascular changes.

A patient with narcolepsy type 1 associated with low CSF hypocretin levels and central hypoventilation was reported to result from infiltration of hypothalamus due to neurosarcoidosis.[25] The analysis of HLA DQB1*0602 was also negative.

Cerebrovascular diseases

There is one case report in the literature, which presented a patient developing narcolepsy following a large ischemic stroke in the hypothalamus.[26] The patient was negative for HLA-DQB1*0602 typing, while hypocretin level in the CSF was demonstrated to be low.

Demyelinating disorders

Symptomatic narcolepsy was reported in patients with immune-mediated neurologic disorders such as multiple sclerosis (MS) with inflammatory lesions in the bilateral hypothalamic region. Less than 20 narcolepsy cases were reported in the literature in patients with MS,[27] while only three patients had demonstrated bilateral lesions in the lateral hypothalamus, with significant reductions in the CSF hypocretin level. In addition, clinical table was resolved following corticosteroid therapy in all these patients with the resolution of hypothalamic lesions. In one case report,[28] narcolepsy-like daytime sleepiness and abnormalities in REM sleep were documented in a patient with MS and hypothalamic demyelinating lesion, which was associated with undetectable hypocretin levels in the CSF. In addition to the presence of hypothalamic lesion and low hypocretin level, symptoms were alleviated upon management of acute MS attack, all of which supported the symptomatic nature of narcolepsy. On the other hand, in spite of low CSF hypocretin levels, cataplexy was not present in these patients. In another paper,[9] five patients with symptomatic narcolepsy secondary to MS were reported; in all these patients, MS has preceded the onset of narcolepsy; all had lesions in the hypothalamus, CSF hypocretin was deficient, but none of them had cataplexy. It was suggested that the absence of cataplexy may be related with acute and sudden onset of the triggering attack and short disease duration.[28]

Narcolepsy was also reported to be associated with bilateral hypothalamic lesions in other demyelinating conditions, as in neuromyelitis optica (NMO).[29] NMO spectrum disorders are characterized by a group of demyelinating disorders associated with antibody for aquaporin 4 (AQP4), which is intensely expressed in hypothalamus. Two patients with symptomatic narcolepsy were reported to be associated with bilateral and symmetrical hypothalamic lesions related with NMO spectrum disorders, and CSF hypocretin level was markedly decreased.[30] Narcolepsy was also reported as the initial presenting manifestation of NMO spectrum disorders.[31] These data were directly linked to the probability of immune attack complexes in the periventricular hypothalamic region caused by the anti-AQP4 antibodies. The authors have further suggested the possibility of other additional antibody-mediated immune mechanisms that may contribute to excessive daytime sleepiness via disturbances in hypocretinergic systems.

Inherited disorders

Narcolepsy type 1 and type 2 were reported to occur in a few inherited disorders. Prader-Willi syndrome is characterized by a range of physiological and psychological abnormalities, which results from the deletion of paternal genes in chromosome 15q11–q13. Excessive daytime sleepiness is commonly associated Prader-Willi syndrome, and even if clinically no narcolepsy is present, decreased levels of CSF hypocretin were demonstrated to be responsible for excessive daytime sleepiness and obesity.[32] Moreover, cataplexy disconnected to narcolepsy may also commonly be observed in Prader-Willi syndrome. In the literature, we detected that 41 patients with Prader-Willi syndrome have fulfilled the diagnosis of narcolepsy.[32],[33],[34] The underlying pathophysiology of sleep problems in these patients was proposed as dysfunction in hypothalamic control on circadian (wakefulness and sleep cycle) and ultradian (non-REM [NREM] and REM sleep cycle) rhythms.

Niemann-Pick disease type C is an inherited lysozomal storage disease characterized by disabling neurological features. Although isolated cataplexy is commonly reported in these patients, diagnosis of narcolepsy is rarely made. The association of low or moderately-low CSF hypocretin levels in Niemann-Pick disease type C was reported in seven patients.[35],[36] Another recent paper reported three patients with narcolepsy type 1 secondary to Niemann-Pick disease type C, one of these patients who had severe cataplexy deceased of disease-related complications.[17] It was suggested that lysozomal storage abnormalities had involved hypocretinergic neurons in the hypothalamus being responsible for isolated cataplexy or additional sleep abnormalities in patients with Niemann-Pick disease.

Neurodegenerative disorders

Disturbances in sleep architecture and sleep disorders are commonly encountered in association with neurodegenerative disorders. Parkinson's disease (PD) is the second most common neurodegenerative disorder, following Alzheimer's disease. Excessive daytime sleepiness was reported up to 30% in PD and to be multifactorial in origin.[37] Although medications, dopaminergic treatments, decreased quality of nocturnal sleep secondary to PD-related factors such as immobility or nocturia, and associated sleep disorders were all suggested to be responsible for hypersomnolence, disease-related intrinsic factors were shown to play a major role in narcolepsy-like excessive daytime sleepiness.[37],[38] Studies measuring CSF hypocretin levels in PD revealed conflicting results,[4],[39],[40],[41] either decreased or normal levels were observed. On the other hand, in a study with immunohistochemical staining in patients with PD,[42] loss of hypocretinergic neurons, together with melatonin-containing neurons, was demonstrated throughout anterior and posterior hypothalamic regions in parallel with PD severity. Low hypocretin levels were also demonstrated in progressive supranuclear palsy and corticobasal degeneration.[40] A negative correlation between lower levels of hypocretin and higher disease duration supports the role of neurodegeneration in the destruction of hypocretinergic neurotransmission.[40],[43] On the other hand, the evaluation of clinical characteristics of these patients on the basis of the revised proposals for narcolepsy,[3],[5] it would be better to classify these conditions as “narcolepsy-like” syndromes instead of secondary narcolepsy [Table 1].

Trauma

Narcolepsy was also reported following trauma and cerebral damage involving both right frontotemporal cortex and hypothalamus.[44] CSF hypocretin was not measured in this case and the presence of cataplexy was not mentioned probably because it was not adequately evaluated due to left-sided hemiparesis. In another case report in the literature,[45] narcolepsy type 2 was reported secondary to marked volume loss in the hypothalamus in addition to involvement of amygdala and brainstem. This patient had no cataplexy and normal levels of CSF hypocretin, and HLA DQB1*0602 typing was negative. In another study, Baumann and et al.[46] conducted an autopsy study in four patients who died of traumatic brain injury and showed that the number of hypocretin neurons has been decreased significantly. These “narcolepsy-like” conditions secondary to brain trauma, in the absence of visible hypocretinergic lesion, should be differentiated from secondary narcolepsy.

Infections

Watson et al. described a patient with narcolepsy type 2 secondary to neurocysticercosis with hypothalamic lesions.[47] CSF hypocretin was reported as normal. This is another example of “narcolepsy-like” condition because of the absence of both cataplexy and hypocretin deficiency.

Autoimmune processes

Although the etiology of the reduction in prohypocretin mRNA-containing neurons has not been thoroughly explained, immunological features such as HLA-DQB1*0602 association, polymorphisms in the tumor necrosis factor (TNF)/TNF receptor genes and in the T-cell receptor, (TCR) locus, and the presence of anti- Tribbles homolog 2 (Trib2) antibodies, as outlined above, suggest an immune-mediated loss of hypocretin-producing neurons.[3],[10],[48] On the other hand, a clear evidence for specific autoantibodies in narcolepsy is missing and it is still not well defined how the first potential triggering factor starts the activation of immune system. It was hypothesized that destruction in hypocretinergic neurons may also be related to the high vulnerability of hypocretinergic neurons to a more systemic autoimmune or inflammatory insult rather than a specific immune-mediated mechanism.[49] It would be wise to concentrate on newly-diagnosed patients or patients with acute-onset disease and very short disease duration to detect possible specific antibodies and activated T-cells in CSF and/or blood.

Vaccinations

The most common triggering factors of narcolepsy are vaccinations and infections. Although symptomatic narcolepsy secondary to vaccinations and infections was suggested in some case reports, it would be challenging for physicians to present a direct causal link between an immune-related triggering factor and narcolepsy. Epidemiologic population-based studies from Europe have shown that the incidence of narcolepsy was 7–13 times higher among people vaccinated with ASO-3 adjuvant H1N1 vaccine than unvaccinated individuals.[50],[51] The molecular mimicry hypothesis between H1N1 virus and hypocretin was failed to be demonstrated, and the cross-reactive autoimmunity against hypocretinergic neurons induced by H1N1 virus itself or vaccination seems insufficient to explain this association. On the other hand, the biological substrate of vaccine-triggered narcolepsy is based on the immunomodulatory effects of vaccination and the strong link between narcolepsy and HLA DQB1*0602 allele.[50]

The question whether vaccination triggers the mechanisms underlying “primary” narcolepsy or narcolepsy occurring following vaccination is of symptomatic type should be carefully elaborated. Sudden onset of excessive daytime sleepiness and cataplexy was reported 4 weeks after H1N1 vaccination (with AS03 as adjuvant), in whom HLA DQB1*0602 was positive and CSF hypocretin-1 was not detectable (<20 pg/ml).[52] In this patient, CSF beta-amyloid was also decreased (275 pg/ml). The authors have concluded that because beta-amyloid modulates the brain response to environmental stressors and has antimicrobial properties, it may play a role in the immunological processes underlying the emergence of narcolepsy following vaccinations. We have reported two patients developing sudden-onset narcolepsy type 1 in two patients following 2–4 months after H1N1 vaccination;[53] one patient had heterozygote loci on HLA DQB1/0602.47 and DQB1/03.01, while the other patient had heterozygote loci on HLA-DQB1/0602.47 and DQB1/02.01, supporting the coexistence of HLA-related immune-related mechanisms in vaccination-related narcolepsy.

Among other vaccinations than H1N1, four patients with narcolepsy were reported following vaccination for flavivirus tick-borne encephalitis.[54] HLA DQB1*0602 was positive in all patients, and CSF hypocretin level was measured in two cases and resulted to be very low. In this vaccine, human albumin is used to reduce interleukin-related side effects and is accused to cause allergic reactions and trigger cross-reactive immune response.

Infections

There are rare case reports in the literature reporting the emergence of narcolepsy in a close temporal relationship with infections. As for vaccinations, it is not easy to differentiate the triggering effects of infections on primary narcolepsy, for which the term secondary narcolepsy should be avoided. This indirect association between infections and the development of narcolepsy supports the role of autoimmunity in the pathophysiology of narcolepsy, rather than a cause-and-effect relationship. There is one case report in the literature, which presents a patient with sudden-onset narcolepsy (type 2) developing 1 week following Dengue fever, a mosquito-borne tropical disease.[55] Cranial MRI was normal and CSF hypocretin was not measured in this patient. Although the authors have suggested the possibility of hypothalamic insult by autoimmune mechanisms secondary to Dengue fever, temporal association by itself may not be satisfying to classify this case report as symptomatic narcolepsy.

Demyelinating disorders

A common underlying etiology for MS and narcolepsy has been suggested as both diseases are well known to be associated with HLA positivity.[56],[57] Although hypothalamic lesions in MS are reasonably related to secondary narcolepsy, a shared susceptibility to develop MS and narcolepsy via autoimmune mechanisms should not be evaluated as symptomatic narcolepsy secondary to MS. Moreover, although HLA-DRB1*15:01 polymorphism constitutes a predisposing factor for both MS and narcolepsy, the strongest association of hypocretin deficiency is linked to HLA DQB1*06:02, which is not much prevalent in MS.[57] On the other hand, four patients with MS were reported to have coexisting narcolepsy,[9] in whom hypocretin deficiency was demonstrated without any lesion in the hypothalamus, and narcolepsy symptoms were all resolved following immune modulatory treatments (including steroids, immunoglobulin, or natalizumab).

Interestingly, on the other hand, a postinfectious immune-mediated insult to hypothalamus was suggested in seven patients with Guillain–Barre syndrome without any lesion in the neuroimaging, on the basis of undetectable CSF hypocretin levels.[58] Because none of these patients had sleep complaints, and objective measures were not performed, the diagnosis of narcolepsy could not be made. Nevertheless, these patients constitute an important basis for the development of narcolepsy secondary to other autoimmune processes. Reduced serum hypocretin levels were also reported in autoimmune encephalitis (patients with antibodies directed against neuronal surface/synapse antigens, N-methyl-D-aspartate receptor [NMDA-R] and leucine rich glioma inactivated 1 [LGI-1]), while none of the patients had sleep complaints and no sleep study was performed.[59] On the basis of these data, we may conclude that there is an increasing support showing the role of aberrant immune regulation and neuroinflammation in the pathophysiology of narcolepsy. In the presence of an appropriate setting, such as genetic and immune-regulatory HLA susceptibility, an insult promoting the disruption of hypocretinergic signaling circuitry may result in unrevealing of the subclinical narcolepsy.

Inherited disorders

Mutations in DNA methyltransferase-1 (DNM-1) gene are linked to autosomal dominant cerebellar ataxia, deafness, and narcolepsy and hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE.[60] Both of these disorders are associated with narcolepsy either type 1 or type 2 with low, intermediate, or normal levels of CSF hypocretin. HLA typing for DQB1*06:02 was normal in all patients. DNM-1 is also expressed in immune cells and required for the differentiation of the lymphocytes. It was suggested that DNM-1 mutations cause dysregulation of immune system and facilitate the formation of autoimmune attack complexes against hypocretinergic neurons. This mutation, interestingly, was not found in patients with “idiopathic” narcolepsy, suggesting that impaired DNM-1 activity deteriorates hypocretinergic system via epigenetic factors.

Trauma

Narcolepsy was reported to develop following head injury in nine patients who were previously asymptomatic.[61] MRIs were all normal. HLA typing was tested in six cases; three patients were reported to be HLA DR2-positive, while two were DR4-positive. Following this paper published in 1994, there are no additional cases in the literature regarding posttraumatic narcolepsy linked with autoimmune pathology. Underlying pathophysiologic mechanisms in these patients are questionable; the sensitivity of neuroimaging may be insufficient to demonstrate a possible hypothalamic lesion, possible insult and axonal injury may have caused the clinical table without being visible on MRI, or trauma may have triggered the narcolepsy in genetically susceptible individuals as shown by HLA-DR positivity. These cases possible constitute “narcolepsy-like” syndromes related with some sort of hypothalamic involvement secondary to trauma or narcolepsy triggered by trauma.

Involvement of other brain regions

In addition to the loss of hypocretinergic neurons in the hypothalamus, neuropathology causing destruction and/or disturbances in the relevant targets of hypocretin may sometimes be associated with narcolepsy-like sleep attacks and/or cataplexy. There are several nuclei in the brainstem which are crucial not only for the control of REM sleep but also for the regulation of behavioral and physiological modifications between wakefulness and sleep.[62] These nuclei receive dense descending inputs from hypothalamic hypocretin-producing neurons and may therefore have an indirect role in the pathogenesis of narcolepsy-like conditions.

Structural pathologies

In the light of these data, structural lesions affecting brain regions other than hypothalamus were reported in the literature to be related with narcolepsy.

Tumors

Three patients have been reported in the literature having narcolepsy due to tumors located in other brain regions than hypothalamus. The first patient was reported in 1977, who had narcolepsy and cataplexy in association with microglioma infiltrating the third ventricle and upper brainstem.[63] Another patient with subependymoma located dorsal to the fourth ventricle and invading tectal midbrain and rostral pons was reported to have secondary narcolepsy.[64] The latter patient was also positive for HLA-DR2. The last patient was reported to develop narcolepsy type 2 after being treated for the choroid plexus carcinoma of the pineal gland.[65] The patient had pinealectomy followed by chemotherapy and radiotherapy. Although one may assume that the radiation treatment may have affected hypothalamic neurons, CSF hypocretin level was demonstrated to be normal (518 pg/ml), and the patient was negative for HLA DQB1*0602. The authors have concluded that symptomatic narcolepsy in this case was secondary to unknown mechanisms unrelated to hypocretinergic system, while further research will be needed for a clarified explanation. Recently, one patient with narcolepsy type 1 secondary to a glioma involving midbrain, third ventricle, and thalamic nuclei and one another patient with narcolepsy type 2 secondary to neurofibromatosis type 1 with glioma infiltrating bilateral optic nerves were reported.[17] The authors have suggested that the rostral projections of hypocretin pathways to forebrain, and caudal projections to the lower brainstem nuclei have probably disrupted to result in clinical symptomatology of narcolepsy.

Although hypocretin deficiency does not mean narcolepsy in all instances, in its absence, the clinical features to make a definitive narcolepsy become even more important than they already are. The absence of typical cataplexy or cataplexy-like episodes[5] together with normal hypocretin levels should hold the physicians off making the diagnosis of secondary narcolepsy but aid the identification of a “narcolepsy-like” condition.

Cerebrovascular lesions

Nokura et al.[66] have reported four patients with narcolepsy-like sleepiness following bilateral paramedian thalamic infarctions. MSLT tests of these patients were positive for narcolepsy and CSF hypocretin levels were within normal limits. Mathis et al.[67] have previously reported that the patients with bilateral paramedian thalamic lesions did not have typical hypersomnolence but presented subwakefulness or dearousal state with an inability to stay fully awake and called this situation as pseudohypersomnia. On the other hand, they have also reported that sleep studies have revealed superficial NREM sleep stages only and no SOREM was demonstrated.

Demyelinating lesions

In demyelinating disorders, projections of hypocretinergic neurons to brainstem structures, basal forebrain, and frontotemporal cortices are commonly affected and may be responsible from secondary narcolepsy.[27] Nevertheless, there is no direct evidence for such an association in the literature, and they should be accepted as “narcolepsy-like” conditions.

Inherited disorders

Myotonic dystrophy is the most common muscular dystrophy with an onset in adulthood. Excessive daytime sleepiness is a very common symptom among patients with neuromuscular disorders. A pathologic MSLT (with a mean sleep latency of less than 8 min) was reported in more than 80% of these patients, while diagnosis of narcolepsy is questionable.[68] Although REM sleep behavior disorder, sleep paralysis, and hallucinations were also reported in these patients, there is no report for the presence of cataplexy and/or hypocretin deficiency. A central dysregulation in wakefulness-sleep regulation was accused in the pathophysiology, due to alterations in diencephalon/brainstem structures and/or connections.

Neurodegenerative disorders

In PD, narcolepsy-like sleepiness was not only attributed to hypocretinergic neuron loss but also to dopaminergic agents and nonergot dopamine agonists.[69] Dopaminergic system was closely linked to the wakefulness, but it was shown in animal models of narcolepsy that the activation and the blockage of dopamine-1 receptors have increased and decreased the sleep attacks, respectively.[70] The activation or blockage of dopamine-2 receptors, on the other hand, has resulted in an increase or a decrease in cataplexy correspondingly, without a major effect on the sleep attacks. These data supply the involvement of nonhypocretinergic mechanisms, namely the involvement of dopaminergic systems, in the pathophysiology of excessive daytime sleepiness, which may explain narcolepsy-like syndromes and cataplexy-like episodes in PD patients with normal CSF hypocretin level. On the other hand, in patients with PD, central dopaminergic dysregulation may also have a triggering and/or additional role for the emergence of narcolepsy-like sleep attacks, in the presetting of a subclinical neuronal loss in the hypothalamic hypocretinergic system.

Trauma

The exact underlying mechanism of narcolepsy developing after head injury is questionable, while the disruption of hypocretin pathways is the most likely explanatory mechanism. Two cases were recently reported in the literature,[17] demonstrating narcolepsy type 1 in both of the patients with traumatic brain injury. In one of these patients, left frontal hyperintense lesion was present in T2-weighted images, while MRI was normal in the other patient. As mentioned above, narcolepsy triggered by trauma could not be excluded.

Autoimmune processes

Parainfectious inflammation

A patient with narcolepsy type 2 was reported following a viral illness, but inflammatory lesions were demonstrated in thalamus and amygdala.[71] HLA DQB1*06:02 was negative and CSF hypocretin was normal. The symptoms of the patient started only 5 days after the upper respiratory tract infection but did not resolve with the improvement of the disease but persisted without any improvement. The authors have suggested that these lesions were more likely resulted from immune-mediated mechanisms. Another case with narcolepsy type 2 and REM sleep behavior disorder was reported in the literature attributed to acute parainfectious brainstem encephalitis.[67] The contrast-enhancing lesions were located in medial pontine tegmentum rostral to fourth cranial nerves. CSF hypocretin level was normal, and HLA studies were negative for DRB1*1501 and DQB1*0602. Because of the absence of both cataplexy and hypocretin deficiency, these cases may be “narcolepsy-like” syndromes, triggered by autoimmune mechanisms following infections.

Paraneoplastic syndromes

Paraspinal neuroblastoma associated with narcolepsy-cataplexy was reported in two cases as a paraneoplastic syndrome.[72] Although the clinical table was resolved in one patient upon surgical removal of the tumor and immunosuppression, the other patient showed devastating course despite aggressive treatment. The underlying mechanism in “paraneoplastic narcolepsy” was hypothesized as the production of hypocretin-like molecules by the tumoral cells triggering an immune-attack complex, which, in turn, cause destruction in hypothalamic hypocretinergic neurons and narcolepsy-like clinical table.


  Conclusions Top


Narcolepsy is the prototype disorder among the central hypersomnolence. Narcolepsy is currently grouped as type 1 and type 2 on the basis of the cataplexy, which is the most pathognomonic feature of narcolepsy type 1 and established to results from the hypocretin (orexin) deficiency in the lateral hypothalamus. Other common features characterizing the REM sleep dissociation such as sleep fragmentation, hypnagogic or hypnopompic hallucinations, and sleep paralysis but are common in both types. In pathophysiologic aspect, either hypothalamic involvement or involvement of the other brain regions may result in narcolepsy. Furthermore, either structural pathologies or autoimmune processes may be responsible from these clinical entities. On this basis, primary (idiopathic) narcolepsy, familial narcolepsy, secondary (symptomatic) narcolepsy, and narcolepsy plus (hereditary forms with additional neurological symptoms) forms may better classify the subtypes of narcolepsy.

Acknowledgments

We shall present our dearest appreciation to Dear Prof. Claudio L. Bassetti for his kind and valuable guidance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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