Brinth, Louise Schouborg

Jennum, Poul Jørgensen

Kornum, Birgitte Rahbek

Mehlsen, Jesper

Torstensen, Eva Wiberg

English

Copenhagen University Research Information System

u n i ve r s i t y  o f  co pe n h ag e n  Københavns UniversitetType 1 narcolepsy is not present in 29 HPV-vaccinated individuals with subjectivesleep complaintsTorstensen, Eva Wiberg; Brinth, Louise Schouborg; Mehlsen, Jesper; Kornum, BirgitteRahbek; Jennum, Poul JørgensenPublished in:Danish Medical JournalPublication date:2018Document versionPublisher's PDF, also known as Version of recordDocument license:CC BY-NCCitation for published version (APA):Torstensen, E. W., Brinth, L. S., Mehlsen, J., Kornum, B. R., & Jennum, P. J. (2018). Type 1 narcolepsy is notpresent in 29 HPV-vaccinated individuals with subjective sleep complaints. Danish Medical Journal, 65(11),[A5510].Download date: 03. Feb. 20201DANISH MEDICAL JOURNALDan Med J 65/11  November 2018 Type 1 narcolepsy is not present  in 29 HPV-vaccinated individuals  with subjective sleep complaints Eva Wiberg Torstensen1, Louise Schouborg Brinth2, 3, Jesper Mehlsen2, Birgitte Rahbek Kornum1, 4 & Poul Jørgen Jennum1 ORIgINAL ARtICLE1) Danish Center for Sleep Medicine, Rigshospitalet-Glostrup2) Syncope Centre, Department of Cardiology, Bispebjerg & Frederiksberg Hospitals 3) Department of Clinical Physiology and Nuclear Medicine, Bispebjerg & Frederiksberg Hospitals4) Molecular Sleep Laboratory, Department of Clinical Biochemistry, Rigshospitalet-Glostrup, DenmarkDan Med J 2018;65(11):A5510Human papilloma virus (HPV) vaccine coverage in girls and women has been dropping markedly in some coun-tries [1, 2]. In Denmark, first-dose coverage of the HPV vaccine dropped from around 80% in 2014 to 45% in 2016 [3]. Concern about the presumed side effects is the commonest reason why [4]. It is estimated that more than 0.5 mill Danish girls and women had re-ceived HPV vaccination by the end of 2015 [5]. A re-port from the Danish Health and Medicines Authority in 2015 showed  a total of 1,305 reported side effects to the HPV vaccine, including 363 that were assessed as serious [5]. Consequently, many researchers have at-tempted to determine whether the reported side effects have any association with the HPV vaccine [6-10]. The majority of the studies show no causal relation, and any association remains unverified [11]. However, despite lack of evidence, still fewer girls and women opt for the vaccination [1]. The most frequently reported side effects are injec-tion-site reactions, headache and fatigue [8]. However, we also noted reports of sleep-related symptoms such as excessive daytime sleepiness, dream activity and  periods of muscle weakness. These symptoms are com-monly seen in individuals with narcolepsy type 1 [12]. This led us to speculate whether HPV vaccination could be associated with the development of narcolepsy type 1. narcolepsy type 1 is a chronic neurological sleep dis-order caused by hypocretin deficiency, which is likely due to autoimmune destruction of hypothalamic hypo-cretinergic neurons [12, 13]. The core symptoms of narcolepsy are excessive daytime sleepiness and signs of rapid eye movement (REM)-sleep dissociation, the most specific being cataplexy. Cataplexy is defined as more than one episode of generally brief (< 2 min.), usually bilateral symmetrical sudden loss of muscle tone with retained consciousness [12, 14]. The devel-opment of narcolepsy type 1 has previously been asso-ciated with another specific vaccine preparation: the Pandemrix H1N1 vaccine [15, 16]. The other variant of narcolepsy – narcolepsy type 2 – is characterised by normal cerebrospinal fluid; as such there is no loss of hypocretinergic neurons and it is not believed to have an immune system-related pathogenesis. For this rea-son, we did not include this or any other sleep dis orders in the analysis.We here aimed to evaluate whether sleep-related symptoms following HPV vaccination could be associ-ated with development of narcolepsy type 1.  There-fore, we conducted a retrospective case-series study of HPV-vaccinated individuals with specific sleep com-plaints. METHODSWe evaluated 29 girls and women with self-reported sleep complaints after HPV vaccination in a retrospect-ive study. At the time, the Syncope Unit at Bispebjerg-Frederiksberg Hospital was the National Centre for HPV vaccine side-effect in Denmark. The Syncope Unit received the majority of references regarding suspected side effect to the vaccine that were of a degree that re-quired assessment at a hospital department. By the end ABSTRACTINTRODUCTION: Human papilloma virus (HPV) vaccine uptake in girls and women is dropping markedly in some countries. Concern about the presumed side effects is the commonest reason why. Reports about side effects include specific sleep complaints such as excessive daytime sleepiness, altered dream activity and periods of muscle weakness. These symptoms are commonly seen in individuals with narcolepsy type 1. We aimed to evaluate whether HPV vaccination was associated with the development of hypocretin-deficient narcolepsy.  METHODS: We report the evaluation for sleep disorders, including narcolepsy, in 29 HPV-vaccinated girls and women who were submitted for evaluation of narcolepsy. All were evaluated by polysomnography and the Multiple Sleep Latency Test, and 18 individuals were also evaluated by measures of cerebrospinal fluid hypocretin-1 concentration. RESULTS: None of the 29 girls and women showed signs of narcolepsy type 1.  CONCLUSION: Our results do not suggest that an association exists between HPV vaccination and the development of narcolepsy type 1. FUNDING: none.TRIAL REGISTRATION: not relevant.2DANISH MEDICAL JOURNAL Dan Med J 65/11  November 2018of the summer of 2015, more than 600 girls and women had been evaluated at the clinic. Some of them had specific sleep complaints: self-reported fatigue, sleepiness, increased dream activity, fragmented sleep and periodic muscle weakness. Thus, in the period from June 2015 to November 2015, the girls and women with sleep complaints were selected. Out of 187 girls and women evaluated for suspected side ef-fects in this period, 29 had specific sleep complaints. These girls and women were clinically referred to the Danish Centre for Sleep Medicine (DCSM) for sleep evaluation on these criteria. Sleep examinations were conducted from July to November 2015. All partici-pants were evaluated with a focused medical interview and a neurological examination assessing: sleep habits, dream activity, hypnogogic hallucination, sleep paraly-sis, cataplexy, fatigue and sleepiness including the Ep-worth sleepiness scale. Further, they were examined with polysomnography (PSG), the Multiple Sleep La-tency Test (MSLT), blood tests and lumbar puncture (including HLA-DQB1*06:02, immunoglobulins, cere-brospinal fluid hypocretin-1 (csf-hcrt-1) level) [17]. The PSG and MSLT were done according to the stan-dard procedure in the clinic [17]. Most of the PSG  were ambulant, but a few were admitted for the  PSG for practical reasons, e.g., due to long transport time.The diagnostic criteria for narcolepsy type 1 are ex-cessive daytime sleepiness for at least three months and presence of one or both of the following: 1. Cataplexy and a sleep latency (SL) of 8 min. or below and two or more Sleep Onset of REM Periods (SOREMPs); 2. A csf-hcrt-1 concentration below 110 pg/ml [12, 13].  We evaluated data on subjective sleep complaints and from PSG in a retrospective study. All girls and women with self-reported sleep complaints were in-cluded in the study and none were excluded. The study was approved by the Danish Health and Medicines Authority. Trial registration: not relevant.RESULTSCharacteristics of the 29 girls and women are shown in Table 1 including sleep-related symptoms reported at medical interview and information about the given HPV vaccine. In addition to the sleep-related symp-toms, all girls and women complained of dizziness and 26 (89.7%) of general muscles weakness. Finally, 21 (72.4%) of the girls and women complained of chronic headache and 21 (72.4%) of muscle and joint pain. One girl did not participate in a medical interview, and therefore her symptoms were not characterised. Data on the HPV vaccine given were available for 27 of the girls and women (Table 1). All the girls and women re-TABLE 2Results from polysomnography, the Multiple Sleep Latency Test, hypocretin and narcolepsy-associated tissue type.Polysomnography (N = 29)Total sleep time, h, median (range) 6.9 (4.0-8.9)Sleep efficiency, %, median (range) 86.8 (48.8-98.1)Sleep latency, h, median (range) 0.39 (0.00-1.95)REM latency, h, median (range) 1.17 (0.41-4.42)Awakenings, n, median (range) 16 (2-66)Multiple sleep latency test (N = 28)Sleep latency, min., median (range) 14.3 (4.4-20.0)Sudden onset of REM sleep, n (%)0/5 sleep periods 15 (53.6)1/5 sleep periods   9 (32.1)2/5 sleep periods   3 (10.7)3/5 sleep periods   1 (3.6)Cerebrospinal fluid (N = 18)Hypocretin-1 concentration, pg/ml, median (range) 407 (338-454)Narcolepsy-associated tissue typePositive for tissue type HLA-DQB1*06:02, n (%) 3 (16.7)REM = rapid eye movement.TABLE 1Characteristics of the girls and women at the time of sleep  evaluation.Anthropometric profiles (N = 29)Age, yrs, median (range) 21.5 (12.8-32.5)BMI, kg/m2, median (range) 20.3 (16.3-30.4)HPV vaccine (N = 27)Time between 1st HPV vaccine dose and  polysomnography, yrs, median (range)4.6 (1.9-7.8)HPV 6-11-16-18, n (%)Brand not specified 21 (77.8)Gardasil   5 (18.5)Gardasil and Silgard   1 (3.7)Questionnaire (N = 28)Epworth Sleepiness Scale score, median (range) 13 (0-18)Sleep-related symptoms, n (%) (N = 28)Fatigue 28 (100)Fragmented sleep 19 (67.8)Sleepiness 16 (57.1)Hypnogogic hallucinations   9 (32.1)Sleep paralysis   4 (14.2)Cataplexy   0HPV = human papilloma virus.3DANISH MEDICAL JOURNALDan Med J 65/11  November 2018 ported symptom onset closely related to the time of their HPV vaccination. The results of the PSGs are shown in Table 2. In general, PSG revealed that all girls and women had a normal distribution of sleep stages, breathing, sinus rhythm and movement pattern. The total sleep time (TST) was less than 6 h in seven of the girls and women.Results of the MSLTs are shown in Table 2. In gen-eral, MSLT were normal in 21 girls and women. We found one woman had abnormal changes: 2 SOREMs and a SL of 6 min.; the TST was 6.6 h. Minor abnormal-ities were found in six women: 1) four girls and women presented with marginal changes in the MSLT; tree had 2-3 SOREMs, but a normal SL of 12-18 min., one had 1 SOREM and a SL of 4 min.; they all had slept more than 6 h during the preceding PSG; and 2) two girls and women had 1 SOREM in the MSLT, with a SL of 8 and 6 min., respectively. However, they had slept less than 6 h during the preceding PSG (5.7 and 5.6 h, respectively). One MSLT was invalid and a repeat was refused.  Csf-hcrt-1 and narcolepsy-associated tissue type were evaluated in 18 girls and women. The results are shown in Table 2. DISCUSSIONWe performed a retrospective analysis of HPV-vaccin-ated girls and women with specific sleep complaints evaluated for narcolepsy type 1 in June-November 2015 at the DCSM. This was a small study of a highly selected group – 29 girls and women with specific sleep complaints out of 187 evaluated for side effects at the Syncope Unit in the same period. None of the HPV-vac-cinated girls and women fulfilled the criteria for a nar-colepsy type 1 diagnosis. Despite reports of muscle weakness, none reported cataplexy; and csf-hcrt-1  levels were normal in all of those examined. The study was not designed to assess with epidemiological tools the prevalence of type 1 narcolepsy in the vaccine group compared with the background population. This would have been difficult to do for several reasons. Ini-tially, the vaccination coverage was very high (> 90%), causing the unvaccinated control group to be very small. Also, such data would be biased due to the low prevalence of narcolepsy type 1, the known diagnostic delay, and the fact that many patients are never diag-nosed. Instead, we report data from a highly selected group of HPV-vaccinated individuals, who were al-ready under evaluation for side effects and primarily suffered from sleep complaints. If there was any associ-ation with narcolepsy type 1, one would expect to iden-tify this association in this particular group of individu-als. Consequently, we believe that HPV vaccination is not associated with narcolepsy type 1. The majority of the girls and women’s PSG and MSLT were normal.  A few girls and women had marginal changes in their PSG and MSLT, but they all complained of insomnia in the period preceding clinical examination, which is likely to produce false-positive results. Further, short SL in MSLT and SOREM episodes occur in 5% of gener-ally healthy girls and women [18], so these findings should be interpreted with caution. Of those examined, three girls and women (17.6%) were positive for the narcolepsy-associated tissue type: HLA-DQB1*06:02. This result is in line with the prevalence in the general population: 12-38% HLA-DQB1*06:02-positive [12]. One participant showed electrophysiological changes suggestive of narcolepsytype 1; she reported periodic insomnia and excessive daytime sleepiness. She did not present with hypnogogic hallucination, sleep paralysis or cataplexy. She was positive HLA-DQB1*06:02, but so are 12-38% of the population. Csf-hcrt-1 was normal (358 pg/ml). Due to the polysomno-graphic findings, we kept her as an out-patient in the DCSM and repeated the PSG and MSLT in June 2017. The examinations were completely normal. Further, at follow-up we did two weeks of actigraphy which on  average showed a total sleep time of 6 h and 22 min. per day.  Our assessment is that the abnormal changes we found in 2015 were caused by sleep deprivation. Follow-up did not raise any suspicion of narcolepsy. An increased incidence of narcolepsy type 1 was  reported after the Pandemrix influenza A (H1N1) vac-cination campaign, especially in Finland, Sweden, Norway and Ireland. We therefore consider it import-ant to report that none of the HPV-vaccinated individu-als we examined had narcolepsy type 1. There was, on average, a long period (4.6 years) between the time at which the girls and women had received the HPV vac-cine and the time at which their sleep evaluations were conducted. They all reported a symptoms onset closely related to time of their HPV vaccination; however, there could be recall bias due to the generally long  period. We find it unlikely, though, that the follow-up is too short and that they might develop narcolepsy type 1 at a later point due to their HPV vaccine. All sub-jects had normal csf-hcrt-1 levels, and as low csf-hcrt-1 is highly sensitive and specific to n narcolepsy type 1, this clearly demonstrates that there were no individuals with narcolepsy type 1 in our cohort.CONCLUSIONOur results do not suggest that an association exists be-tween HPV vaccination and the development of narco-lepsy type 1.CORRESPONDENCE: Eva Wiberg Torstensen.  E-mail: eva.wiberg.torstensen.01@regionh.dkACCEPTED: 24 August 2018.CONFLICTS OF INTEREST: Disclosure forms provided by the authors are available with the full text of this article at Ugeskriftet.dk/dmj4DANISH MEDICAL JOURNAL Dan Med J 65/11  November 2018LITERATURE1. Statens Serum Institut. Decline in the uptake of HPV vaccination, 2016. www.ssi.dk/Aktuelt/Nyheder/2016/2016%201%20hpv_fald.aspx (19 Dec 2016).2. Ueda Y, Enomoto T, Sekine M et al. Japan‘s failure to vaccinate girls against human papillomavirus. Am J Obstet Gynecol 2015;212:405-6.3. Skorstengaard M, Thamsborg LH, Lynge E. Burden of HPV-caused can-cers in Denmark and the potential effect of HPV-vaccination. Vaccine 2017;35:5939-45.4. Nicol AF, Andrade CV, Russomano FB et al. HPV vaccines: a controver-sial issue? Braz J Med Biol Res 2016;49:e5060.5. Danish Health and Medicines Authority. Report from the Danish Health and Medicines Authority for consideration by EMA and rapporteurs in relation to the assessment of the safety profile of HPV-vaccines. Dan-ish Health and Medicines Authority, 2015. 6. EMA. HPV vaccines: EMA confirmes evidens does not support that they CRPS or POTS. EMA, 2016, 12 Jan.7. Brinth LS, Pors K, Theibel AC et al. Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus. Vaccine 2015;33:2602-5.8. Goncalves AK, Cobucci RN, Rodrigues HM et al. Safety, tolerability and side effects of human papillomavirus vaccines: a systematic quanti-tative review. Braz J  Infect Dis 2014;18:651-9.9. Luna J, Plata M, Gonzalez M et al. Long-term follow-up observation of the safety, immunogenicity, and effectiveness of Gardasil in adult women. PloS One 2013;8:e83431.10. Nicol AF, de Andrade CV, Russomano FB et al. HPV vaccines: their  pathology-based discovery, benefits, and adverse effects. Ann Diagn Pathol 2015;19:418-22.11. Molbak K, Hansen ND, Valentiner-Branth P. Pre-Vaccination care-seek-ing in females reporting severe adverse reactions to HPV vaccine. PloS One 2016;11:e0162520.12. Kornum BR, Knudsen S, Ollila HM et al. Narcolepsy. Nat Rev Dis Primers 2017;3:16100.13. 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;59:1553-62.14. American Academy of Sleep Medicine. International classification of sleep Disorders, 3th ed. Darian, IL: Amarican Academy of Sleep Medi-cine, 2014.15. Partinen M, Kornum BR, Plazzi G et al. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol 2014;13:600-13.16. Wijnans L, Lecomte C, de Vries C et al. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pan-demic and vaccination campaigns. Vaccine 2013;31:1246-54.17. Knudsen S, Jennum PJ, Alving J et al. Validation of the ICSD-2 criteria for CSF hypocretin-1 measurements in the diagnosis of narcolepsy in the Danish population. Sleep 2010;33:169-76.18. Mignot E, Lin L, Finn L et al. Correlates of sleep-onset REM periods dur-ing the Multiple Sleep Latency Test in community adults. Brain 2006;129:1609-23.

Type 1 narcolepsy is not present in 29 HPV-vaccinated individuals with subjective sleep complaints

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Type 1 narcolepsy is not present in 29 HPV-vaccinated individuals with subjective sleep complaints

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