by Anoop K. Gupta, MBBS; Swapnajeet Sahoo, MD; and Sandeep Grover, MD
Dr. Gupta is a junior resident, Dr. Sahoo is a senior resident, and Dr. Grover is a professor in the Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Funding: No funding was received for the preparation of this article.
Financial Disclosures: The authors have no conflicts of interest relevant to the content of this article.
Abstract: Narcolepsy is an uncommon sleep cycle disorder with a usual onset in adolescence, but it is often misdiagnosed and underdiagnosed. Rarely is the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis seen in patients. The clinical characteristics of narcolepsy are often confused with many psychiatric and neurologic disorders. Lack of clinical awareness about narcolepsy leads to frequent prescriptions of antiepileptics and psychotropics, which can adversely affect the quality of life of children and adolescents. We report a case of an adolescent male who presented with all four cardinal symptoms of narcolepsy and had been misdiagnosed with epilepsy, psychosis, and depression. We discuss various issues regarding narcolepsy in children and adolescents.
Keywords: narcolepsy, adolescence, misdiagnosis
Innov Clin Neurosci. 2017;14(7–8):20–23.
Narcolepsy is an uncommon sleep cycle disorder characterized by the tetrad of chronic excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis.1 The cardinal symptom of paroxysmal sleep is seen in all patients, whereas other symptoms such as cataplexy (70%), hypnagogic hallucinations (25%), and sleep paralysis (5%) are less consistent. Usually, patients experience some, but not all, of these four symptoms, and this tetrad occurs in <10 percent. Additionally, symptoms might suggest abnormal REM sleep.2–5
The incidence of narcolepsy usually peaks in adolescence or early adulthood, and the prevalence rate in the general population varies from 0.03 to 0.16 percent across studies from different countries.6–8 Although narcolepsy has been reported to begin before the age of 10 years in a substantial number of children, it is often underdiagnosed and misdiagnosed.9 The disorder is known to have bimodal peak age of onset, with a larger peak at around 15 years of age and a smaller peak at approximately 36 years of age.10 Lack of clinical awareness about different presentations in children and adolescents often leads to misdiagnosis of narcolepsy as schizophrenia, epilepsy, and other neurological disorders. This also often leads to prescription of antipsychotic and antiepileptic medications, which are not required.
In this report, we present a case of an adolescent male with all four cardinal symptoms of narcolepsy who was misdiagnosed with epilepsy, psychosis, and depression. We also discuss various issues regarding narcolepsy in children and adolescents.
Mr. A, an 18-year-old man, presented to psychiatry outpatient services with excessive daytime sleepiness of approximately 1.5 years’ duration. When the chronology of symptoms was evaluated, it was evident that about 1.5 years before presentation, the patient had an episode of high-grade fever (101–103?F) and was empirically treated for typhoid and malaria. Within a week of the fever episode while on antibiotics and antimalarial medications, he started experiencing excessive daytime sleepiness (EDS), i.e., despite good sleep at night, he started sleeping for 5 to 6 hours during the daytime, with total sleep duration/day being 15 to 16 hours/day. If not woken, he would continue to sleep for 19 to 20 hours/day. Initially, family members attributed his sleepiness to weakness from the fever and medications and did not consider it important. Because of continued EDS, the patient was unable to study, and this led to academic decline. He would often attempt to keep himself awake but would fall asleep between activities like studying, watching television, eating, etc. About three months after developing EDS, he started to notice that whenever he would laugh out loud or get angry, he would experience a sudden feeling of generalized body weakness, especially in the upper part of his body, along with ptosis of both eyes and flexion of the head. In addition, he would have a sudden bending of his knees, leading to imbalance if he was standing, and would also have difficulty speaking. At times, he could not control his posture and would fall. He often would drop things during these episodes. This entire phenomenon would last for 8 to 10 seconds after the particular emotional reaction, following which he would have complete recovery within 10 to 15 minutes without any deficits. There was no history of loss of consciousness, loss of vision, tonic-clonic movements, or urinary or fecal incontinence during such episodes.
During the same time, while the patient would fall asleep, he could see an unknown boy standing near him that others could not see. He would describe it as visualizing an unknown boy touching his chin in gray-color film with open eyes in clear consciousness along with normal visualization of his family members. While experiencing these hallucinations, the patient would not be able to move his limbs or speak; such episodes of inability to move his limbs or speak would last for 5 to 10 minutes. The same phenomenon would at the time also be experienced while he was coming out of sleep. At times while he was asleep, others would notice him laughing or tightening his lower limbs, but he would not have the memory of it later.
Over the period of the next year, the symptoms continued to increase. All of these symptoms led to significant socio-occupational dysfunction, and he became distressed. He was seen by multiple physicians, including neurologists and psychiatrists, and was diagnosed with viral encephalitis and other disorders, such as epilepsy, schizophrenia, and depression. He was treated with tablet modafinil 100 to 150mg/day, capsule fluoxetine 40mg/day, tablet risperidone 2mg/day, antiepileptics (tablet lamotrigine tablet and levetiracetam), tablet duloxetine, and tablet clonazepam in various combinations with no improvement in symptomatology. Investigations in the form of an electroencephalogram (EEG) and magnetic resonance imaging of the brain revealed no abnormalities. Serum immunoglobulin assay revealed measles IgG at 1.35 AI (>1.1: significant); he had been vaccinated as per the Universal Immunization Programme (UIP) of India, but details were not available.
Throughout the patient’s history, there was no evidence of any first rank symptoms, depressive features, signs and symptoms suggestive of hypothyroidism, tonic-clonic movements, drug abuse, forgetfulness, hyperphagia, hypersexuality, hyperorality, obsessive compulsive symptoms, skin picking behavior, or impulsivity. There was no positive family history of any sleep disorders.
His physical examinations revealed no abnormalities, and on mental status examination, he appeared to be very distressed due to his symptoms. However, there was no evidence of depression, and he denied any first rank symptoms and obsessive compulsive symptoms. His investigations in the form of hemogram, liver function test, renal function test, serum electrolytes, thyroid function test, and repeat EEG revealed no abnormalities. His score on the Epworth Sleepiness Scale (ESS) was 15, which suggested significant impairment.
Based on the history, a diagnosis of narcolepsy was considered. All of the previously prescribed medications were stopped, and he was started on tablet methylphenidate 5mg/day, which later was increased to 10mg/day. The patient and family members were informed about the disorder. Within three weeks of starting methylphenidate, all of his symptoms subsided. After one month of methylphenidate therapy, he resumed his studies. He has remained symptom free for the last two years since starting methylphenidate.
Whenever a child, adolescent, or young adult subject presents with excessive sleepiness, narcolepsy must always be considered as a differential diagnosis. However, in routine clinical practice, because of the low prevalence rate, clinicians do not consider narcolepsy as a differential diagnosis and often expose young patients to various anticonvulsant, antipsychotic, and antidepressant medications. As seen in the literature, many times patients with EDS are mistaken as lazy or to have disorders like attention deficit hyperactivity disorder, conduct disorder, oppositional-defiant disorder, depression, mental retardation, and generalized absence-like epileptic seizures.11 The cataplexy seen in narcolepsy is often mistaken for syncope, atonic-type epileptic seizures, or psychological symptoms like dissociation.12 The hypnagogic hallucinations of narcolepsy are often misunderstood as hallucinatory psychotic symptoms as seen in patients with schizophrenia, temporal lobe epilepsy, night terrors, nightmares, or panic attacks.11 The sleep paralysis is often confused with dissociative episodes, intense fatigue, or certain neuromuscular diseases.13 The patient in this case had all of the cardinal symptoms of narcolepsy, but he still was misdiagnosed and treated with antiepileptics, antipsychotics, and antidepressants, supporting the very fact that narcolepsy usually is misdiagnosed and there is a delay in diagnosis.
No definitive explanation exists regarding the higher incidence of narcolepsy during adolescence. One hypothesis suggests that during childhood and adolescence, individuals’ responses to infections (streptococci or viruses) provoke an autoimmune reaction that elicits the symptoms of narcolepsy. However, more studies are needed to test this hypothesis.12 The temporal association of an infection prior to the onset of EDS in this case can be considered as an indicator to support this hypothesis.
Environmental factors, such as infections, pregnancy, brain trauma, and stress, might precede the onset of symptoms in up to 50 percent of cases.14 Studies on narcolepsy in children and adolescents have demonstrated a link between narcolepsy and infections with Streptococcus pyogenes and H1N1 influenza, as well as H1N1 vaccination. Many authors have suggested that infections and vaccine antigens might be important triggers of autoimmune attacks to the central nervous system.15–20 IgG abnormalities also have been reported in patients with narcolepsy.21 More recently, the HLA-DQB1*0602 allele has been linked with narcolepsy, which was earlier associated with streptococcal infections.22,23 The patient in this case also had infection (as evident in a high-grade fever) prior to the onset of EDS and had abnormal IgG levels, which support the aforementioned facts. Certain biological factors also have been linked with narcolepsy. Genetic studies on patients with narcolepsy have well established a strong association of narcolepsy with the HLA-DQB1*0602 allele.24 In routine clinical practice, it is not mandatory to carry out genetic testing to establish the diagnosis of narcolepsy. Of all biological factors, hypocretin deficiency has been associated with the etiopathogenesis of narcolepsy. The hypocretinergic system is predominantly excitatory and exerts effects on the monoaminergic (dopamine, norepinephrine, serotonin, and histamine) and cholinergic systems.25 The underlying pathophysiology in narcolepsy is a loss of hypocretin-producing cells in the posterior hypothalamus. In narcoleptic patients, especially those with cataplexy (85% to 90%), significantly low cerebrospinal fluid levels of hypocretin are found,26–29 and hypocretin deficiency also has been associated with HLA-DQB1*0602.30 In short, both biological and environmental factors contribute to the development of narcolepsy.
Several reports suggest that hypnagogic and hypnopompic hallucinations can be misinterpreted as a psychotic illness like schizophrenia.31,32 Many times, it becomes very difficult to distinguish the hypnagogic and hypnopompic hallucinations seen in narcolepsy from the hallucinations of schizophrenia. Careful clinical evaluation (Table 1) can help in distinguishing the disorders. Most studies suggest that the psychotic symptoms of narcolepsy tend to have no response to antipsychotics, leading to a diagnosis of refractory schizophrenia, as happened with this patient. One should be quite prudent before starting symptomatic management with antipsychotics in children and adolescents, and proper negative history should be taken to rule out sleep-related disorders. Another common misdiagnosis in cases of narcolepsy is epilepsy, and proper identification is essential for appropriate treatment (Table 1).
A nocturnal polysomnographic sleep study followed by multiple sleep latency tests can be used to confirm the diagnosis of narcolepsy, especially when the disorder is first being diagnosed, before treatment has begun, and if hypocretin deficiency has not been documented. However, an overnight sleep study is not mandatory to confirm the diagnosis, and this should only be considered in cases where the diagnosis is in doubt. An overnight sleep study must be performed after the individual has stopped all psychotropics, following two weeks of regular sleep-wake patterns as documented by sleep diaries. In this case, we were not able to perform the sleep study, as the patient was on multiple medications and was in significant distress during the time of presentation, and the diagnosis was not in doubt.
Stimulants (methylphenidate) and wakefulness enhancers (modafinil) are the first-choice drugs for the management of narcolepsy. Modafinil (100–150mg/day) was tried in this case, but there was no improvement. A recent meta-analysis of studies of modafinil use in patients with narcolepsy suggests that it is efficacious in reducing EDS but not cataplexy.33 Thus, modafinil was not tried again in this case. On the other hand, stimulants like methylphenidate have been found to be quite safe and efficacious in treating narcolepsy,34–36 which was also exemplified in this case.
- Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154–166.
- Shorvon SD. Handbook of Epilepsy Treatment. John Wiley & Sons; 2010.
- Aran A, Einen M, Lin L, et al. Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep. 2010;33(11):1457–1464.
- Sullivan SS. Narcolepsy in adolescents. Adolesc Med State Art Rev. 2010;21(3):542–55, x – xi.
- Akintomide GS, Rickards H. Narcolepsy: a review. Neuropsychiatr Dis Treat. 2011;7:507–518.
- Longstreth WT, Koepsell TD, Ton TG, et al. The epidemiology of narcolepsy. Sleep. 2007;30(1):13–26.
- Hublin C, Partinen M, Kaprio J, Koskenvuo M, Guilleminault C. Epidemiology of narcolepsy. Sleep. 1994;17(8 Suppl):S7–12.
- Nishino S. Clinical and neurobiological aspects of narcolepsy. Sleep Med. 2007;8(4):373–399.
- Kothare SV, Kaleyias J. Narcolepsy and other hypersomnias in children. Curr Opin Pediatr. 2008;20(6):666–675.
- Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology. 2001;57(11):2029–2033.
- Stores G. The protean manifestations of childhood narcolepsy and their misinterpretation. Dev Med Child Neurol. 2006;48(4):307–310.
- Coelho F, Aloe F, Moreira G, et al. Narcolepsy in childhood and adolescence. Sleep Sci. 2012;5(4):139–144.
- Britton T, Hansen A, Hicks J, et al. Guidelines on the diagnosis and management of narcolepsy in adults and children. In: Evidence-Based Guidelines for the UK with Graded Recommendations. Ashtead, UK: Taylor Patten Communications Ltd; 2002.
- Dauvilliers Y, Tafti M. Molecular genetics and treatment of narcolepsy. Ann Med. 2006;38(4):252–262.
- Wijnans L, Dodd C, de Ridder M, et al. Pandemic influenza vaccine & narcolepsy: simulations on the potential impact of bias. Expert Rev Vaccines. 2016;15(5):573–584.
- Ahmed SS, Schur PH, MacDonald NE, Steinman L. Narcolepsy, 2009 A(H1N1) pandemic influenza, and pandemic influenza vaccinations: what is known and unknown about the neurological disorder, the role for autoimmunity, and vaccine adjuvants. J Autoimmun. 2014;50:1–11.
- Sturkenboom MCJM. The narcolepsy-pandemic influenza story: can the truth ever be unraveled? Vaccine. 2015;33 Suppl 2:B6–13.
- Aran A, Lin L, Nevsimalova S, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep. 2009;32(8):979–983.
- Ambati A, Poiret T, Svahn B-M, et al. Increased ?-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases. J Intern Med. 2015;278(3):264–276.
- Lopes DA, Coelho FMS, Pradella-Hallinan M, et al. Infancy narcolepsy: Streptococcus infection as a causal factor. Sleep Sci. 2015;8(1):49–52.
- Tanaka S, Honda M. IgG abnormality in narcolepsy and idiopathic hypersomnia. PloS One. 2010;5(3):e9555.
- Longstreth WT, Ton TGN, Koepsell TD. Narcolepsy and streptococcal infections. Sleep. 2009;32(12):1548.
- Tafti M, Lammers GJ, Dauvilliers Y, et al. Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. Sleep. 2016;39(3):581–587.
- Chabas D, Taheri S, Renier C, Mignot E. The genetics of narcolepsy. Annu Rev Genomics Hum Genet. 2003;4:459–483.
- Black JE, Brooks SN, Nishino S. Conditions of primary excessive daytime sleepiness. NeurolClin. 2005;23(4):1025–1044.
- Nishino S, Ripley B, Overeem S, et al. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol. 2001;50(3):381–388.
- Krahn LE, Pankratz VS, Oliver L, et al. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status. Sleep. 2002;25(7):733–736.
- Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59(10):1553–1562.
- Dauvilliers Y, Baumann CR, Carlander B, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry. 2003;74(12):1667–1673.
- Han F, Lin L, Schormair B, et al. HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep. 2014;37(10):1601–1608.
- Bhat SK, Galang R. Narcolepsy presenting as schizophrenia. Am J Psychiatry. 2002;159(7):1245.
- Talih FR. Narcolepsy presenting as schizophrenia: a literature review and two case reports. Innov Clin Neurosci. 2011;8(4):30–34.
- Golicki D, Bala MM, Niewada M, Wierzbicka A. Modafinil for narcolepsy: systematic review and meta-analysis. Med Sci Monit. 2010;16(8):RA177–86.
- Mahowald MW, Bornemann MAC. Stimulants and narcolepsy. Sleep. 2005;28(6):663.
- Billiard M. Narcolepsy: current treatment options and future approaches. Neuropsychiatr Dis Treat. 2008;4(3):557–566.
- Hirai N, Nishino S. Recent advances in the treatment of narcolepsy. Curr Treat Options Neurol. 2011;13(5):437–457.
- Sinha S, Brady M, Scott CA, Walker MC. Do seizures in patients with refractory epilepsy vary between wakefulness and sleep? J Neurol Neurosurg Psychiatry. 2006;77(9):1076–1078.
- Gangdev P, Dua V, Desjardins N. Isolated sleep paralysis and hypnic hallucinations in schizophrenia. Indian J Psychiatry. 2015;57(4):383–385.
- Liddon SC. Sleep paralysis, psychosis, and death. Am J Psychiatry. 1970;126(7):1027–1031.
- Gross-Tsur V, Manor O, van der Meere J, et al. Epilepsy and attention deficit hyperactivity disorder: is methylphenidate safe and effective? J Pediatr. 1997;130(4):670–674.
- Baptista-Neto L, Dodds A, Rao S, et al. An expert opinion on methylphenidate treatment for attention deficit hyperactivity disorder in pediatric patients with epilepsy. Expert Opin Investig Drugs. 2008;17(1):77–84.
- Hedges D, Jeppson K, Whitehead P. Antipsychotic medication and seizures: a review. Drugs Today. 1998 2003;39(7):551–557.