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.