Case: 12-year-old with Hallucinations

00:00 In this talk, we're going to review narcolepsy. Let's start with a case. This is a 12-year-old who presents for evaluation of multiple complaints. The patient initially began seeing ghost when falling asleep at night starting several months ago. Over the past 2 months, her school performance has declined. Her teachers will find her asleep in class. At one point after the fire alarm went off, the patient collapsed in the middle of the classroom. There was no seizure-like movement and she awoke in normal health after this event but was agitated. Her parents initially attributed these symptoms to her poor sleep. The past week, she has had an episode where she woke up but was unable to move for several minutes and had to just lay in her bed.

00:47 Concerned, her parents have brought her in for evaluation. So, what's the most likely diagnosis? Is this narcolepsy, seizure disorder, migraine, or schizophrenia? Well, this is not consistent with a presentation of schizophrenia. The patient does have hallucinations but there are other symptoms in this case suggestive of an alternative diagnosis. This is not consistent with a presentation for migraine.

01:16 Migraine can cause paroxysmal neurologic symptoms, but again there are other features occurring in this patient; cataplexy, sleep paralysis that raise a strong suspicion for an alternative diagnosis. This is not the presentation of a seizure disorder. The patient had a paroxysmal episode in school and seizure would be in the differential diagnosis for this patient, but it is not explained the constellation of findings including cataplexy and sleep paralysis. This patient is presenting with the typical clinical constellation of a diagnosis of narcolepsy. The patient has hypnagogic hallucinations, cataplexy, sleep paralysis, all of which are characteristic of this condition.

03:32 So let's talk about narcolepsy. Let's review a definition of what it is, talk a little bit about the pathophysiology, how we diagnose and manage these patients. First, let's start with a definition. Narcolepsy is a sleep disorder marked by daytime sleepiness and it is associated with 3 important clinical episodes. The first is cataplexy. These are emotionally triggered loss of muscle tone. As a result of a startle, a loud noise, or something that startles the patient, the patient will lose muscle tone and may drop all the way to the floor. The second is hypnagogic hallucinations. We remember that hypnagogic hallucinations are hallucinations when patients are going to sleep and we can see auditory or tactile hallucinations that occur right when the patient is falling asleep. These are differentiated from hypnopompic hallucinations which occur upon awakening. And then last is sleep paralysis. This is very disconcerting for patients, a brief period of immobility, inability to move upon awakening. Patients wake up, they're fully conscious but they are unable to move their body and this typically last for short minutes, after which tone resolves and patients are able to move normally. When we classify narcolepsy, we can classify it as narcolepsy type 1, type 2, and secondary narcolepsy and this will be important in terms of our diagnostic investigations. Where does narcolepsy come from? What causes it? Well, there are a number of brainstem structures that are involved in getting us to go to sleep and maintaining sleep and making sure we're awake and not asleep during the day.

05:19 When we think about those important brain structures, we start with the lateral hypothalamus. This produces orexin which is an important wakefulness promoting hormone and substance in the brain. The lateral hypothalamus speaks to the tuberomammillary nucleus which sends descending projections to the raphe nuclei and the locus coeruleus which in turn send projections to the multiple neurotransmitter systems to turn the brain on and promote wakefulness. So in this way, we see that the hypothalamus and brainstem controls our level of arousal.

05:55 In narcolepsy, loss of neurons in that lateral hypothalamus is the primary cause of narcolepsy type 1. And this will be important in diagnosing these patients, we'll look at orexin levels and see a reduction in the orexin levels that is diagnostic of narcolepsy type 1. Abnormalities in this system also contribute to narcolepsy type 2 and secondary causes of narcolepsy. When we think about narcolepsy type 1, there are both genetic and environmental factors that contribute to this condition.

06:29 Genetic factors include certain forms that are familial and in particular mutations in the DQB1 gene. 96% of patients with this haplotype will also have orexin deficiency and so in narcolepsy type 1 we see orexin levels are low and this is contributing to the symptoms and syndrome in this patient. There are also environmental triggers, neurons that produce orexin, maybe destroyed due to an autoimmune process triggered after strep infection or a strep pharyngitis or certain types of flu and could trigger the development of narcolepsy type 1. In terms of narcolepsy type 2 and secondary narcolepsy, in narcolepsy type 2 orexin levels are normal. There is dysfunction in that circuit, the inability to maintain wakefulness but it does not result from a reduction or degeneration or attack on orexin- producing neurons in the hypothalamus and the etiology is poorly understood.

07:28 There are also secondary causes of narcolepsy where there is an underlying lesion.

07:33 We think about things like tumors, strokes, vascular malformations, inflammatory processes such as sarcoidosis which can cause a basal meningeal irritation and this also may be associated with various genetic syndrome such as Prader-Willi syndrome. And here, we see loss of that posterior hypothalamus function and midbrain circuitry.

08:55 In terms of epidemiology, narcolepsy type 1 and 2 are uncommon with the prevalence of 25-50/100,000. There is an equal predominance in men and women for narcolepsy type 1 and we typically see this occurring and beginning in the early teenage years in the 20s. In terms of clinical features, the common feature in these patients is daytime sleepiness. This is the most common symptom of all types of narcolepsy. Patients may have sleeping at inappropriate times as opposed to excessive sleeping, they just sleep at times that is inappropriate. They may have sleep attacks where they fall asleep with no warning sign, lasting less than 30 minutes and usually they wake up well rested in the morning, but again have these sleep attacks occurring during the day. Cataplexy can be seen in 60-70% of patients. Again, these are these emotionally triggered episodes where patients transiently lose muscle tone and become weak. It may be triggered by intense laughing or anger or a startle or loud noise. Patients lose tone often beginning in the face and this may progress to a full drop attack where the patient is on the ground, atonic, extremely weak for a short period of minutes. The patient is conscious, this usually last around 2 minutes, and 60% of patients will present within 5 years of onset of the disease with symptoms of cataplexy.

10:31 How about hypnagogic hallucinations? These are auditory or sometimes tactile hallucinations that occur as patients are going to sleep. Patients may describe frightening; visual, tactile and sometimes auditory hallucinations that occur again while falling asleep, not while waking up. Sleep paralysis is quite uncommon, less than 5% of patients, but extremely burdensome and worrisome for patients.

11:01 Patients will describe upon awakening that they are awake and fully conscious but unable to move their body, typically lasting less than 2 minutes and this results from disconnection between the brain circuits that allow the brain to awake and turn the brain on and then those that return muscle tone from REM sleep. And that disconnection between those 2 systems results in wakefulness of consciousness but inability to return tone for those first couple of minutes upon awakening.

12:04 How do we diagnose narcolepsy? Well, this is really a clinical diagnosis supported by polysomnography and other diagnostic testing. Polysomnography and narcolepsy demonstrates spontaneous awakening, reduced sleep efficiency and often increased light non-REM sleep. REM sleep often begins within 15 minutes so we see early onset REM sleep in these patients. Patients have a deficiency of REM sleep and so they push REM sleep earlier into the night to try and recover REM sleep that has been lost but the diagnostic modality of choice for diagnosing narcolepsy is the multiple sleep latency test and this is really a test I want you to remember and associate with the diagnosis of narcolepsy. To make a diagnosis of narcolepsy, we want to look at the findings that we see on the MSLT. The MSLT is done the morning after a sleep study or polysomnogram. The patient is placed in sleep- inducing environments and allow to fall asleep spontaneously multiple times. Each nap session continues for about 15 minutes after sleep onset to detect when REM sleep begins after the onset of a nap. Typically, REM sleep begins many minutes into a nap and in narcolepsy we see early onset REM. Each nap each sleep episode is repeated at 2-hour intervals until the patient has had 4-5 opportunities to nap.

13:41 And patients with narcolepsy take less than 8 minutes to fall asleep and have early onset REM during those naps. In terms of laboratory investigations, we can also do CSF studies and gene testing to evaluate particularly narcolepsy type 1. In the CSF, we can measure orexin levels and that's that hormone released by the hypothalamus that is reduced and deficient in patients with narcolepsy type 1. We see low levels that are suggestive of narcolepsy type 1 and this is typically done when sleep testing cannot be performed. CSF analysis is not required to establish a diagnosis of narcolepsy type 1, but when performed and demonstrating low orexin levels is highly suggestive of this condition. Genetic testing for that DQB1 gene and abnormalities polymorphisms in that gene can also be performed. Other test may be supportive of this diagnosis, but again the MSLT is how we diagnose narcolepsy. Actigraphy or the use of a movement sensor worn on the patient's non-dominant wrist can be helpful to evaluate sleep time and sleep efficiency and we see reduced sleep efficiency in narcolepsy. So there are a number of diagnostic criteria to establish a diagnosis of narcolepsy type 1. The first is daily periods of irrepressible need to sleep, 3 times per week for more than 3 months. So for a persistent period of time patients have this frequent need to sleep during the day.

15:15 We also need to establish 1 or both of the following; low levels of orexin in the cerebrospinal fluid or cataplexy and an MSLT of less than 8 minutes demonstrating that early onset of sleep in the MSLT. For narcolepsy type 2, there are a number of criteria that are used to establish this diagnosis, daily periods of irrepressible need to sleep, a mean sleep latency of less than 8 minutes. Again, that MSLT finding. Here are typically cataplexy is absent. There are normal levels of orexin in the cerebrospinal fluid. We don't need that to establish a diagnosis of narcolepsy type 2, but the presence would be suggestive of this type of narcolepsy.

16:00 And the findings should not be better explained by other causes like insufficient sleep, obstructive sleep apnea which is ruled out on a polysomnogram, delayed sleep phase disorder, or effects of medications, illicit substances or withdrawal from a medication.

16:47 When we're managing patients with narcolepsy, the goal of therapy is to improve alertness so that performance is optimized and make sure patients are safe and both of those need to be adequate for normal activities of daily life. There are a number of things we think about in managing patients with narcolepsy. The first is safety, 2nd sleep hygiene. We think about maintaining regular and adequate sleep schedules. Schedule of naps can be helpful and avoiding substances that may precipitate attacks. We want to avoid medications that may worsen sleepiness and you can see some of those here. And monitor for other comorbidities, psychiatric disorders, and obesity can also be seen in this condition. Pharmacotherapy can be used to manage the symptoms of narcolepsy.

17:38 There is no disease modifying therapy but we manage the symptoms of sleep paralysis and cataplexy and excessive daytime sleepiness. Modafinil is the first line agent for promoting wakefulness, is a wakefulness promoting agent. It's a non-amphetamine CNS stimulant so it's a stimulant that doesn't work on by stimulating the systemic circulation but by changing neurotransmission to promote wakefulness and it's typically well tolerated with low abuse potential. The second line agents are the amphethamines and methylphenidate. These are preferred in children. There is slightly higher risk of hypertension, tachycardia, psychosis, anorexia, and abuse with these agents. There are also some newer options for patients not tolerating either of the first or second line therapies and that includes solriamfetol recently approved in 2019. This is a selective dopamine and norepinephrine reuptake inhibitor. And pitolisant approved in 2020. It's an oral histamine inverse agonist. When we're treating cataplexy, we aim to suppress REM sleep by increasing norepinephrine and serotonin. And so we can look at a number of agents that are helpful in preventing and treating cataplexy. The SNRIs, tricyclic antidepressants, sodium oxybate is approved and is really the drug of choice for severe cataplexy. It mediates the effect on gaba receptors and pitolisant. And here you can see a table describing some of the common agents that are used in patients with narcolepsy, their mechanism of action, and important side effects. And you don't need to understand and remember all of the side effects but have a general appreciation for how these drugs work and some of the side effects that can be seen. Modafinil is extremely well tolerated. It can cause light headaches, occasionally anorexia, and nausea. And there is really rare abuse potential. This is the first line agent for treating patients with narcolepsy. Sodium oxybate is our agent of choice for severe cataplexy. It is restrictive in its prescription due to abuse potential but can be quite helpful in patients, again, who have severe cataplexy which is particularly disabling and distressing for patients. Amphetamines are very useful and efficacious but need to be considered with their high risk of abuse. And pitolisant is very well tolerated but has been associated with headaches, insomnia, nausea and QT-QTC prolongation.