Table 1The patient’s polysomnographic findings
Her sleep architecture was unusual in that sleep latency was slightly shorter than normal (2 min), with an 11-minute REM latency and sleep fragmentation. The multiple sleep latency test (MSLT), which consisted of four naps (20-minute sessions, 2 hours apart), showed sleep on all naps with an average sleep onset latency of 1.5 min (normal ~10 min). She had sleep-onset REM periods (SOREMP) in three of four naps.

Diagnosis

Based on these findings and her typical symptoms for narcolepsy and cataplexy, she was diagnosed with type 1 narcolepsy.

Treatment, Outcome, and Follow-up

She initially received modafinil and venlafaxine, to which she partially responded.
Since her symptoms did not resolve completely, we prescribed methylphenidate as an add-on with which she experienced moderate improvement but not complete resolution of her symptoms.
Discussion :
Our patient, a woman in her mid-thirties, presented with excessive daytime sleepiness, episodes of cataplexy, sleep paralysis, and increased REM-associated features throughout the day. All her symptoms had started immediately after recovery from COVID-19. The results of polysomnography (PSG), including MSLT, confirm the diagnosis of narcolepsy syndrome. Our patient developed the symptoms at an older age compared to most patients who are diagnosed in their early twenties14. Also, she experienced the full range of possible symptoms in narcolepsy, which is another uncommon finding15.
The Academy of Sleep Medicine suggests a diagnosis of NT1 in patients with cerebrospinal fluid hypocretin deficiency; alternatively, the academy recommends the diagnosis of NT1 in patients with clear-cut cataplexy in line with PSG and MSLT findings that show mean sleep latency shorter than 8 minutes and at least two SOREMs16. Our patient was diagnosed with NT1 based on her characteristic symptoms and a shortened mean sleep latency (MSL=1.5 minute) on MSLT, and SOREMPs in 3 of 4 recordings. These findings predict CSF hypocretin deficiency and may be used a surrogate for CSF hypocretin deficiency 14,17.
The European guidelines on the management of narcolepsy recommend either sodium oxybate or a combination of antidepressants and stimulants as the first line of treatment for patients with narcolepsy-cataplexy18. Our patient showed only a partial response to the initial treatment with venlafaxine and madafinil. In such cases, the guideline recommends switching to sodium oxybate. However, since sodium oxybate is not available in Iran, we added methylphenidate, which enhanced the preexisting response to medications.
The pathophysiology of type 1 narcolepsy involves the autoimmune destruction of hypocretin-producing neurons in the lateral hypothalamus. This mechanism is supported by the strong association of HLA DQB1*0602 phenotypes with the development of narcolepsy 9. Numerous articles have reported the development of narcolepsy in patients with the HLA DQB1*0602 phenotype following infections, especially streptococcal infections and flu11,12,19-21. Of note, an increase in the incidence of narcolepsy was reported during the 2009 H1N1 influenza pandemic and after massive flu vaccination in some countries12,22-24, especially among people younger than 18 years and in France, Denmark, Finland, and Sweden 22. However, studies from South Korea, Canada, England, Netherlands, and Spain did not show a significantly increased risk associated with H1N1 vaccines 25,26. The discrepancy in the effects of vaccination across different populations may be caused by the interplay between genetic predisposition and environmental factors in the development of narcolepsy.
The exact autoimmune processes that cultivate narcolepsy remain to be explained. Initial hypotheses were focused on specific antibodies27-32; however, recent findings more strongly support a T-cell-mediated cellular damage in patients with specific polymorphisms in alpha locus of the T-cell receptor33,34. The damage inflicted by T-cells following infections may be triggered via molecular mimicry or as a side effect of systemic hyper-activation of the immune system and cytokine storms4,8. Our patient developed typical symptoms of narcolepsy-catalepsy after infection with COVID-19; this concurrence may point to an underlying autoimmune or para-infectious process causing sleep disruption in our patient.
A recent review article has emphasized the important potential role of SARS-CoV2 infection as a triggering factor for narcolepsy35.
COVID-19 infection has shown several neurologic manifestations such as encephalitis, stroke, headache, Seizures, and Guillain–Barrè syndrome10. Although the exact mechanism of the neurologic damage associated with SARS-CoV-2 is unclear, suggested mechanisms include systemic inflammatory response, immune-mediated injury, direct neuroinvasion, and microvascular damage 10. The same mechanisms, and most probably an immune-mediated injury may have contributed to cell damage in the lateral hypothalamus in our patient.
Coronavirus infection and its resultant cytokine storm can increase the permeability of the blood-brain barrier making the brain more susceptible to the effects of systemic inflammation as well as migration of T-cells 36. The patient’s HLA phenotype has been shown to affect the type of symptoms and their severity in COVID-1937. Unfortunately, we could not perform HLA typing in our patient due to financial limitations. However, it is possible that specific HLA phenotypes may predispose to narcolepsy following COVID-19. Olfactory dysfunction is another interesting concurrence in narcolepsy and COVID-19 . COVID-19 has been shown to affect the olfactory bulb probably by viral invasion and inflammation causing anosmia and parosmia10,35,38. Narcolepsy is also frequently associated with olfactory dysfunction that responds to intranasal orexin39. Still, the role of olfactory dysfunction as a mediating factor in the development of narcolepsy is unknown35,39. Our patient experienced olfactory dysfunction during the course of COVID-19; However, her taste and smell had recovered by the time she started experiencing sleep issues. We postulate that primary infection and inflammation of the olfactory bulb with SARS-COV2, by recruiting T-cells, may have played a role in the pathogenesis of narcolepsy via immune sensitization to hypocretin-producing cells.