Narcolepsy

Narcolepsy is a chronic sleep disorder characterized by irregularity and malfunction of sleep cycles. Excessive daytime sleepiness is one of the leading symptoms of narcolepsy, even if the individual is receiving enough sleep during the night. REM sleep in narcoleptics is regular, but with an earlier onset of 5 minutes after falling asleep. Most people do not experience the REM sleep cycle until an hour or more after falling asleep. Moreover, narcoleptic individuals may experience properties of REM sleep in the awake state, such as hypnagogic hallucinations and cataplexy (loss of muscle tone). The biological marker underlying the molecular basis of narcolepsy is a low or an untraceable level of the cerebrospinal fluid, hypocretin 1, in the hypothalamic neurons. Moreover, the onset of narcoleptic phenotype is strongly associated with the onset of cardiovascular status such as lower arterial blood pressure. [15]It has been evidenced that specific conditions that are more favourable to the onset of narcolepsy include an increase in an individual’s risk due to certain genetic conditions or to the enhanced autoimmune characteristics of the disease itself [7]. Narcoleptic patients also exhibit structural changes in grey and white matter, including changes in the volume of various brain regions as the disorder progresses [12]. Due to the chronic nature of narcolepsy, patients can be considerably, though not completely cured if an early diagnosis is achieved.

Dee Daud's channel on narcoleptic experience
http://youtube/eCYYxN8byAk

1 Causes

1.1 Genetic Conditions

1.1a Missense mutation in Myelin Oligodendrocyte Glycoprotein (MOG) and Human Leucocyte Antigen (HLA)

Narcolepsy has been found to be tightly linked with HLA (Human Leucocyte Antigen) haplotype on chromosome 6, which is present in over 95% of narcoleptic patients with cataplexy. The HLA haplotype is necessary and prominent among narcoleptic patients’ chromosome 6 exon, but not sufficient to induce narcolepsy, as approximately 20% of the healthy population used as control subjects bear the same haplotype. Therefore, other mutations on the genome must contribute to the genetic basis of narcolepsy. Hor et.al performed population-based, genome-wide association studies (GWAS) of familial sporadic narcolepsy [1].

Missense Mutation on MOG
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Fig 1. Localization of wildtype MOG at perinuclear membrane (A and C).
Clustered membranous localization of mutated MOG-GFP gene in cytoplasm (B and D) (Hyun et,al. 2011)

They hypothesized that there is a causal relationship between DQB1 allele (the allele from HLA class 2 regions), and the pathogenesis of sporadic narcolepsy such that it amplifies susceptibility to narcoleptic phenotype by up to 50-fold [1]. To classify a contributory mutation underlying narcolepsy, linkage analysis was performed on chromosomes 4 and 21 of families with a narcoleptic background. The low titer of hypocretin 1 in the cerebrospinal fluid of affected members within the family further strengthened the diagnosis. Genotypes of DNA samples of the affected and unaffected family members were sequenced using Affymetrix genome-wide SNP arrays. HLA genotyping revealed that associated DQB1 allele was expressed by the half proportion of the affected members on the pedigree, but other affected members carried a different DQB1 allele, suggesting that this specific allele is insufficient to explain the genetic basis of the narcolepsy [1].
Another possible mutation was recognized on HCRT allele, which is involved in the hypocretin system. Nevertheless, pathogenic mutation was not uncovered from the sequencing of the coding region of HCRT and its two receptors. These findings therefore rejected the HLA class II and HCRT genes as universal genetic causes underlying narcolepsy. The genome-wide linkage analysis discovered noteworthy linkage on chromosome 6 [1]. Further investigation detected 148 missense SNV (single nucleotide variants) on chromosome 6, in the gene encoding MOG (myelin Oligodendrocyte), a myelin antigen containing Ig-like domains [1]. A missense mutation caused nucleotide substitution of guanine for cytosine, altering the amino acid sequence from serine to cysteine. This mutation was detected specifically on the MOG gene of affected members, while no unaffected members carried this mutation. The pathogenicity of this mutation becomes further evident when critical epitope region networking with demyelinating monoclonal antibodies is interrupted. The two cysteines containing Ig-like domain of control members’ MOG genes form a disulfide bond; therefore, the functional MOG protein is made. However, when an extra cysteine is produced, a protruding cysteine within the disulfide bond is formed. This further interrupts the proper folding process. Clustered localization of the mutated MOG protein was also observed in the cytoplasm, suggesting the pathogenic nature of the mutation [1] (Fig.1).
Additionally, findings by Hor et,al. emphasized the key role of oligodendrocytes in narcolepsy by outlining glial cell involvement.

1.1b Mutation in Orexin Receptor Type2 (OX2R) leading to decreased CSF Orexin level

Orexins are expressed by two receptors, OX1R and OX2R. OX2R is another key factor involved in the regulation of wakefulness. Willie JT et al. found that mice lacking OX2R fall asleep quickly with the increased pressure on maintaining wakefulness [2]. Moreover, OX2R antagonists are recognized to enhance sleep [3].

Orexin Signalling
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Fig 2.
Loss of orexin signaling at TMN neurons from OX2R TD mice.
But restoration of OX2R function is observed at TMN neurons from OX2RTD x Zp3-Cre mice (D).
Optimal firing activity at TMN neurons from OX2R TD x Zp3-Cre mice like control (E). (Mochizuki et,al, 2011)

Cre immunoreactive neuron imaging
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Fig 3. Staining of Cre- immunoreactive neurons at TMN and adjacent regions (A).
localization of OX2R in cerebral cortex, thalamus, hippocampus, and TMN/ SuM area (B1).
Confined localization at TMN/SuM area after AAU-GFP injection in OX2R TD mouse (B2).
Extended wake bout lengths in OX2R TD mice with AAU-Cre injection at TMN-SuM area.
No improvement in wakefulness in a group with AAU-Cre injection into thalamus (D). (Mochizuki et,al)

OX2R acts upon many brain regions that are involved in wake promotion such as histaminergic neurons, monoaminergic region and cholinergic systems. The study done by Mochizuki et,al. hypothesized that orexins advance wakefulness through OX2R in histaminergic systems and adjacent regions [4].
Poor maintenance of wakefulness was also exhibited with fragmented sleep in OX2R TD mice. Non-REM sleep in OX2R TD mice occurred more frequently in shorter periods compared to the control. OX2R TD mice displayed increased sleep drive with more frequent transitions from wake into NREM sleep [4]. Transgenic mice are produced with a transcription disruptor gene (OX2R TD) that inhibits expression of functional OX2R [4].
Patch clamp recording of TMN neurons is performed directly to test the function of disrupted OX2R. Basic electrophysiological properties of TMN neurons were indistinguishable in WT and OX2R disrupted mice. However, patch clamp recording showed that orexin signaling was not detected at TMN due to disrupted OX2R expression. To see if the disrupted expression of OX2R can be restored, crosses between OX2R TD mice with Zp3- Cre are carried out. The previously disrupted OX2R function was restored after the crossing and orexin signaling was later observed [4] (Fig 2).
These mice had fully normal sleep behavior, with extended wakeful periods and decreased sleep drive. Since Cre was expressed within the female germline, TMN neurons from the offspring that lacked the functional OX2R gene expression had restored responses to orexin-A permanently throughout development.
To see if the focal and localized rescue of OX2R signaling in TMN region can fully recover the wake/ sleep cycle and fragmented wakefulness, microinjections of AAV-Cre were delivered. AAV-Cre microinjections noticeably enhanced the level of wakefulness during the dark period at the region where TMN neurons are localized and adjacent regions, but failed to improve wakefulness globally [4] (Fig.3). Although local microinjections normalized the pattern of wakefulness, mice continued to exhibit fragmented sleep [4] (Fig 3).
Therefore, it is evident that consolidation of sleep is regulated by other regions, but not at the posterior hypothalamus where TMN neurons are localized. As a result, the study highlights the importance of orexin signaling in the TMN region of the posterior hypothalamus and demonstrates that OX2R in the TMN region is involved in orexin signaling and is sufficient for the maintenance of wakefulness. Unlike the complete orexin-KO mice, OX2R TD mice had less severe narcoleptic phenotypes [4]. A lack of OX2R signaling resulted in moderate to severe sleepiness or partial narcoleptic phenotype.

1.2 Molecular Basis

1.2a Decreased CSF Histamine level

Excessive daytime sleepiness (EDS) is the recognized symptom among chronic sleep related disorders such as narcolepsy, idiopathic hypersomnia, and behaviorally-induced insufficient sleep syndrome (BIISS). Gradual loss of hypothalamic neurons producing the neurochemical, hypocretin, is the signature molecular marker among narcoleptic patients with cataplexy [5]. These neurons send out projections and further activate neurons involved in monoaminergic, cholinergic, and histaminergic pathways. Histaminergic neurons of hypothalamic tuberomammillary nucleus (TMN) are the major wake-promoting system within the brain that gets stimulated by hypocretin [6]. Histaminergic neurons are involved in wakefulness, with a maximal firing capacity during arousal [6].

CSF Histamine level
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Fig 4. EDS patients exhibited lower CSF histamine level coparedto non- EDS patients. ( Bassetti et,al. 2010)

Interruptions of histamine synthesis of histaminergic neurons increase the sleep pressure and decrease the maintenance of wakefulness. Animal studies suggested that sole effect of perfusion of hypocretin is insufficient in promoting wakefulness [6]. Huang et al. recognized that histamine promotes the waking effect by triggering the action of histamine H1 and H3 receptors [7]. Therefore, H3 receptor agonists enhanced wakefulness by directly increasing the histamine release presynaptically [7]. By realizing the major role of hypocretin and histaminergic neurons in promotion of arousal, Bassetti, et al. measured CSF histamine levels of three groups: patients with narcolepsy, other forms of EDS and control without EDS [6].
Lumbar punctures were executed in order to obtain CSF samples of subjects. Hypocretin-1 levels in the CSF were calculated and compared to the mean value using radioimmunoassay. CSF Histamine levels were measured using ultrasensitive ultra performance liquid chromatography (UHPLC) method with mass spectrometry detection. The hypocretin and histamine levels of 4 groups were compared with the mean CSF values. Patients with narcoleptic cataplexy represented levels of CSF hypocretin-1 lower than the detection limit. Unlike hypocretin-1 levels, histamine levels were above the detection limit, but patients with EDS exhibited considerably low level of histamine compared to the ones without EDS [6] (Fig. 4).
Therefore, inverse correlation was shown between CSF histamine levels and EDS severity. Consequently, histaminergic transmission is altered in humans with EDS-related disorders, including narcolepsy. Particularly in patients with narcolepsy, lower CSF histamine levels can explain the gradual loss of hypocretin neurons, because hypocretin directly innervates histaminergic neurons. However, a clear causal relationship between hypocretin and histamine levels cannot be concluded, as CSF histamine levels are also reduced in EDS conditions with standard hypocretin levels [6]. In summary, low CSF histamine levels were exhibited among EDS subjects due to possible interactions between histaminergic neurons with different monoaminergic systems involved in wakefulness. Due to the findings on alteration of CSF histamine level, drugs such as H3 receptor agonists were put forward as a possible treatment of EDS-related disorders such as narcolepsy and those with other origins.

1.2b Elevated Tribbles Homolog 2- specific antibody leading to autoimmune response

Trib-2 specific antibody titer
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Fig. 5 Mean Trib2- Specific antibody titer in control is represented by dotted horizontal line.
Higher titer of antibody in patients of narcolepsy-cataplexy. (A)
Trib2 specific antibody titer decrease within first 2-3 years but higher titer is remained stable compared to control. (B)
(Lopes et,al 2010)

Hypocretin-producing neurons play crucial roles in the regulation of sleep and maintenance of wakefulness. Currently, it is hypothesized that loss of hypocretin neurons is due to autoimmune characteristics of the disorder. Therefore, it is assumed that there is a specific peptide acting as the autoantigen within the hypothalamus. However, experiment done by Overeem et,al. found that immune processes do not occur directly on either hypocretin ligands or their receptors [9].
The study performed by Lopes et al. proposed that tribbles homolog 2 (Trib2) is the peptide concentrated in the hypocretin-producing neurons at the posterior hypothalamus which acts as the autoantigen and is targeted by its monoclonal antibodies [8].
To test whether autoimmune relationships are present within hypocretin-producing neurons in the hypothalamus, transgenic mice are generated to track gene expression of hypocretin neurons. The hypocretin coding sequence is displaced with a flag-tagged polyA binding protein to bind to the mRNA of hypcretin cells [8]. Therefore, expression of the hypocretin gene can be detected by coimmunoprecipitating with an anti-flag antibody . ELISA assay was carried out to observe the presence of autoantibodies against Trib2 in the CSF of narcoleptic patients. Narcoleptic patients displayed high titers of autoantibodies against Trib2 compared to the control [8] (Fig.5).
At the onset of narcolepsy, the titer of antibodies in CSF is increased compared to the control. Sharp decreases in concentration of Trib2 antibodies were shown within the first 2-3 years [8] (Fig.5). Trib2-specific antibody concentration was positively correlated with regularity of cataplexy onset and severity of EDS (Excessive Daytime Sleepiness). Moreover, when the hypothalamic region of mice is double-stained with narcolepsy- cataplexy patient’s serum that contains high titer of the antibodies and anti- hypocretin antibody, immunoreactivity was observed, indicating that Trib2 specific autoantibodies target hypocretin neurons [8]. Since autoimmunity is involved in the nature of narcolepsy, a novel treatment, immunotherapy, is suggested in an attempt to restore the CSF hypocretin level when the patient is diagnosed early.

2 Structural changes

2.1 Cortical Thinning

Numerous neuroimaging techniques have been used to illustrate the pathophysiology of narcolepsy. A study done by Joo et,al. utilized F-fluro deoxyglucose positron emission tomography (PET) and single photon emission computed tomography (SPECT) to examine the brain function of narcoleptic patients [10]. Subjects were individuals diagnosed with narcolepsy with cataplexy, but with no history of taking central nervous system stimulants.
The mean value of the measured cortical thickness of the narcoleptic patients with cataplexy was much lower than that of the control [10] (Fig. 6).

Cortical Thickness
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Fig 6. Significant decrease in cortical thickness of narcoleptic patients
is shown compared to control. (Joo et,al 2011)

Localized cortical thinning was detected in the dorsolateral frontal gyri, orbitorectal gyri, medial frontal gyrus, cingulated gyrus, insular cortex, inferior temporal gyri, and posterior parietal lobule [10]. No brain regions of narcoleptic patients were detected by increased cortical thickness. However, it is insufficient to draw an association between cortical thickness and duration of EDS or cataplexy, both symptoms of narcolepsy.
Many narcoleptic patients exhibit memory loss with an accompanying attention deficit as one of leading symptoms, following cataplexy and EDS. The Dorsolateral prefrontal cortex and parietal cortex house the systems involved in attention networks within the brain [10]. Noticeable cortical thinning within the inferior parietal lobule and medial and dorsolateral prefrontal cortex can explain the attention deficit exhibited by narcoleptic patients. Moreover, the level of cortical thinning in the left supramaginal gyrus correlates with the severity of EDS the patient experiences [10]. Another leading symptom indicating narcolepsy is depression. PET studies of patients with depressive disorders showed decreased cortical volume and activity in the frontal cortex [10]. Therefore, the cortical thinning of the orbitofrontal gyri of narcoleptic patients might explain why depression is experienced. Moreover, depression was shown to be negatively associated with the cortical thickness of patients’ left parahippocampal gyri [10] (Fig. 7).

Depressiveness vs Cortical Thickness
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Fig 7. Negative correlation is drawn between depressive symptoms and cortical thickness of parahippocampal gyrus. (Joo et,al 2011)

Narcoleptic patients also experienced emotional deregulation besides depression. The anterior cingulate and ventromedial prefrontal cortex is involved in maintaining emotional processing, with connections to the insular cortex, basal ganglia, and limbic structures [10]. The SPECT study also showed the increased volume of cerebral perfusion in the premotor cortexes, and sensorimotor cortexes during cataplexy [11]. Moreover, emotional maintenance systems, cingulate, fronto- temporal areas and insula are overactivated in response to emotional changes that may generate cataplectic pathways [11].
Consequently, it is concluded a neuroanatomic change, cortical thinning, catalyzed disturbances in attention, emotion, memory and sleepiness of narcoleptic patients with cataplexy.

2.2 White and Gray matter abnormalities

Conventional structural brain imaging has until now failed to classify constant abnormalities in patients with narcolepsy-cataplexy. Diffusion Tensor Imaging (DTI) and Voxel based morphometry (VBM) were used in detecting intrinsic structural reorganization and signal alteration in grey and white matter in the study done by Scherfler et al [12]. Mean diffusivity is used as the parameter of brain tissue integrity, and fractional anisotropy (FA) is used as a parameter of neuronal fiber integrity. Increased mean diffusivity at the hypothalamus coincided with the loss of hypocretin-producing cells as the underlying cause of narcolepsy. [12] (Fig. 8)

Increased mean diffusivity (MD)
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Fig 8. MD values noticeably increased in orbital cortex (A), hypothalamus (B), and cingulated (C) of patients of narcolepsy. (Scherfler et,al 2012)

Noteworthy changes in DTI with decreased FA signal were detected in the hypocretinergic projection sites to cortical areas including cingulated cortex, inferior and superior temporal cortices and inferior orbital cortex [12] (Fig. 9).

Decreased Fractional Anisotrophy (FA)
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Fig. 9 Decreased FA is observed within regions of frontal superior orbital gyrus (A), Inferior temporal gyrus (C) and axonal tracts within anterior cingulated (D).
(Scherfler et,al 2012)

Moreover, the SPECT study also depicted hypometabolism in the hypothalamus of narcoleptic patients [13]. Increases in mean diffusivity at the ascending arousal system, including dorsal raphe and ventral tegmental areas were detected [12]. Further increased diffusivity in these systems is explained by their status as major projection sites of hypocretin neurons from the posterior region of the hypothalamus. Decreased FA signal was recognized in the orbito-frontal cortex and this explains both axonal and neuronal damage at the region due to the exhaustion of barriers to water motion [12]. The same effect was observed within the regions of anterior and posterior cingulated cortex, leading to reductions in gray and white matter. Increased mean diffusivity was shown in the superior temporal gyrus, which contains the primary auditory cortex. This also showed the extended latency of auditory-induced potentials in narcoleptic patients. Significant decreases in FA levels of the inferior temporal cortex were also exhibited in association with the primary visual cortex. Consequently, processing of visual information was impaired by reduced capacity of recognition memory in patients with narcolepsy. Therefore, parameters such as FA and MD for diffusion tensor imaging techniques clarify the presence of axonal and neuronal damages throughout various regions of the brain in narcolepsy-cataplexy subjects.

3 Cardiovascular Change

Diastolic BP
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Higher proportion of narcoleptics compared to the control were diastrolic non-dippers.
The sleep related decrease in BP is not shown.

Decreased arterial blood pressure among hypocretin-deficient rodents during wakefulness, compared to the control has been hypothesized as one measure of cardiovascular status. Administration of hypocretin stimulants recognizably elevated the arterial blood pressure of narcoleptic mice [14]. The study done by Dauvilliers et.al hypothesized that there is a intricate interaction between sleep-wakefulness and blood pressure such that hypocretin deficiency may increase the cardiovascular risk [16]. Ambulatory blood pressure monitoring displayed decreased daytime diastolic BP, lower detection level pressures in the arteries, and heart rates of narcoleptic patients compared to the control. Moreover, non-dipping diastolic blood pressure patterns, conditions where sleep-related declines in blood pressure occur, are found in narcoleptic patients. [15] (Fig. 10)
Therefore, it can be suggested that the hypersomnia exhibited by narcoleptic patients is the main contributor of disregulation of night-to-day cardiovascular function.
This finding is matched by the previous study done by Bastianini et al., which shows that differences in blood pressure during wakefulness and sleep states were evident among HCRT (hypocretin neuropeptide precursor) deficient mice compared to control [15]. Moreover, further increases in blood pressure during REM sleep were recognized in narcoleptic mice. Therefore, chronic lack of HCRT signalling further results in disregulation of blood pressure.

4 Treatments

Narcoleptic Treatments
W. Vaughn McCall, M.D., M.S.(GHSU)
Department of Psychiatry and Health Behavior
Georgia Health Sciences University
http://youtube/c-M06I48-Vk

Many treatments for EDS related disorders such as narcolepsy and hypersominias are still facing challenges. Treatments of narcolepsy based on hypocretin deficiency and involving pharmacotherapies such as CSN stimulants, antidepressants, sodium oxybate, etc. are more well-recognized. However, treatments for other hypersomnias are more demanding due to the indeterminate origin of the disorder. Since narcolepsy is a chronic disorder, lifelong treatment is needed. Narcoleptic patients with cataplexy benefit the most from combined drug therapy with accompanying behavioural modification [17].

4.1 Amphatamines

Amphetamines are derivatives of catecholamines, and are made more lipophilic in nature to increase their capacity in entering the central nervous system. They target catecholaminergic pathways in the brain by acting directly on presynaptic regions; causing more monoamines to be released and elicit increased response [17]. Amphetamine derivatives effect on dopaminergic, adrenergic, and serotonergic synapses [17]. Moreover, amphetamines are further modified by the addition of a methyl group to increase their potency in crossing the CNS. Amphetamines are effective in promoting wakefulness and reducing cataplexy, but can be addictive and have the side effect of causing anxiety. Other side effects include vasoconstriction and increased heart rate and blood pressure.

4.2 Modafinil

Modafinil, another drug approved by FDA for narcolepsy, is also prevalently used in clinical cases. Unlike amphetamines, Modafinil is insoluble in water and therefore less potent. A study done by Mignot tested whether modafinil binds the DAT (dopamine reuptake site) transporter and see if modafinil acts through dopamine reuptake inhibition [17]. Wake-promoting effects could not be detected in DAT knockout mice. Therefore, modafinil also incorporates primary dopaminergic mediation in promoting wakefulness. One advantage of modafinil is that it has low risk of abuse due to its low solubility and low potency. This low risk of addiction makes Modafinil more easily available to patients.

4.3 Sodium Oxybate

Sodium Oxybate is the most well known treatment for narcolepsy, and provokes slow wave and REM sleep. Since many patients suffer from disturbed nocturnal sleep, sodium oxybate treatment decreases sleep pressure during the day and enhances wakefulness. However, it has short half life and low potency and so is administered more frequently or at night with another drug. It is most widely used for clinical purposes because it is equally effective on most symptoms of narcolepsy. Sodium oxybate acts on GABA-B receptors, inducing sedation [17]. However, its use is limited by its side effects and poor public reputation. It is easily produced for recreational use, and sometimes used for criminal purposes due to its strong sedative effect. Moreover, sodium oxybate treatment can be followed by strong withdrawal symptoms. The most common side effects caused by sodium oxybate are nausea and weight loss.

Bibliography
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18. Daud Dee, (2008, August 11) Channel 5TV: My Day out with Narcolepsy Part 2. http://www.youtube.com/watch?v=eCYYxN8byAk
19. Global Medical Education, (2012, August 19) Treatments for Narcolepsy. http://www.youtube.com/watch?v=c-M06I48-Vk

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