Re: BMJ: Safety of AS03-adjuvanted split-virion H1N1 (2009) pandemic influenza vaccine: a prospective cohort study
Country/regulatory agency:
Ireland
HSE
WHO wer report
Preliminary Reports
(Hyperlinked resources)
28th March 2011 Re: Possible association between use of Pandemrix ...
Result of report:
Note HSE : 25 confirmed as of April 2012
WHO wer. 2013- RR 13.0 per 100 000 (95% CI: 4.8–34.7) in Ireland
Association:
Casual relationship pending further investigations
Conclusion:
In January 20111 Pandemrixx was removed from GP offices due to change in Seasonal and pandemic vaccines recommendation from NAIC and not due to necrolepsy
Limitations:
Investigation pending!
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Country/regulatory agency:
Sweden
Medical products Agency (MPA) 2010
Back ground:
Swedish registry cohart study, based on a 5.3 million population, comparing the risk of narcolepsy in vaccinated versus unvaccinated individuals from October 2009 through December 2010.
Preliminary Reports
(Hyperlinked resources)
Pandemrix and narcolepsy - preliminary report 2011-03-28
http://www.lakemedelsverket.se/upload/nyheter/2011/PandemrixRegReport110328.pdf
Result of report:
The study shows a 3-4-fold increased risk for children and adolescents vaccinated with Pandemrix to be diagnosed with narcolepsy as compared with unvaccinated subjects (4,06 cases per 100*000 person years in vaccinated children/adolescents compared with 0,97 cases per 100*000 person years in unvaccinated). This risk would translate into an absolute risk of three cases of narcolepsy in 100*000 vaccinated children/adolescents. No increased risk was seen in adults
Association:
Plausible (interim)
Conclusion
MPA suspended Pandemrix use pending investigation
Limitations:
Methodological limitations definition of risk time for observation and of onset of disease. Of both Sweden and Finnish studies differed
Differences between the two populations (socio-demografic etc) are not corrected for in this analysis.
One weakness of the current study is that some cases may not yet be registered in the databases
An important caveat with the present study is that the incidence of narcolepsy is based on the time of diagnosis rather than the time of onset of disease. MPA estimates of incidence may be biased if the time interval between disease onset and a registered diagnosis has been shortened during the study period.
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Country/regulatory agency:
Sweden
Medical products Agency (MPA) 2011
Back ground:
On 30 June 2011 the Medical Products Agency (MPA) in Sweden published the results of a case inventory carried out by the MPA in Sweden during 2009-2010 [1]. The study presents evidence to support a link between having been vaccinated with Pandemrix and narcolepsy in children and adolescents 19 years and younger.
Preliminary Reports
(Hyperlinked resources)
Narcolepsy – Case inventory study in Sweden 2009-2010 1(20)
MPA June 30, 2011
http://www.lakemedelsverket.se/upload/nyheter/2011/Fallinventeringsrapport_pandermrix_110630.pdf
Also see :
Thursday, June 30, 2011
Report from an epidemiological study in Sweden on vaccination with Pandemrix and narcolepsy
Result of report:
The incidence rates of narcolepsy varied by age, being around 2 per 100,000 in the 0 to 9 year age group, 3.5 in the 10 to 14 year age group and 1.7 in the 15 to 19 year age group.*
Overall the incidence rate in those vaccinated was 4.2 versus 0.64 in unvaccinated per 100,000 person-years, respectively suggesting a relative risk of 6.6 (95% CI 3.1 -14.5) and an absolute risk of 3.6 (95% confidence interval 2.5 – 4.7) additional cases per 100,000 vaccinated cases or 1 case per 27,800 vaccinations (from 1 per 21,300 to 40,000 vaccination).
Association:
Temporal association
Conclusion:
Subjects who had been vaccinated with Pandemrix were at a 6.6‐fold increased risk to develop narcolepsy with cataplexy compared to those who had not been vaccinated.
Cases of narcolepsy with cataplexy with onset after vaccination had a higher prevalence of cataplexy as a first symptom and of two or more simultaneous symptoms as compared with non‐vaccinated cases.
Further research is urgently needed to explain the possible causative mechanisms.
Limitations:
The study did not differentiate between vaccinated and un-vaccinated cases. (ECDC comment)
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19904
However this limitation was covered in preliminary reports in 2010 above!
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Country/regulatory agency:
Finland
National Institute for Health and Welfare (THL)
Back ground:
Prevalence is estimated to be 0.026 %, one in four thousand will fall ill with narcolepsy 1-4 newly diagnosed cases per 100 000 inhabitants per year (children and adults together). This means that in Finland approximately 60-70 persons have been diagnosed with narcolepsy annually
Genetic factors i.e twins 6/11,000 (non-identical 311,000)
Preliminary Reports:
(Hyperlinked resources)
Statement from the National Institute for Health and Welfare of Finland of 1 February 2011
Result of report:
The incidence of narcolepsy had gradually increased during
the years 2006–2009: in 2006, a total 44 cases were diagnosed, while in 2009 the total number of new narcolepsy cases was 68.
incidence of narcolepsy among those vaccinated was 9.2-fold higher in comparison to those not vaccinated (95% confidence interval 4.5–21.4).
Association:
Plausible (Interim)
Conclusion:
Interim results
Final report due 31 August 2011
24 August 2009 National Advisory Committee on Vaccination in Finland (KRAR) and THL delivered a statement THL advised upon KRAR’s recommendation that as a precautionary measure, Pandemrix should not be given without a specific risk assessment of the treating physician, until more information about the association between the vaccine and narcolepsy was available
Limitations:
The study did not identify any increased risk in adults and other associations of vaccines
Genetic factors explained well however not applied to study!
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Country/regulatory agency:
Finland
National Institute for Health and Welfare (THL)
Preliminary Reports:
(Hyperlinked resources)
Association between Pandemrix and narcolepsy confirmed among Finnish children and adolescentsIn its final report, the National Narcolepsy Task Force confirms the tentative conclusion published last January. 1 Sep 2011
Result of report:
In its final report, the National Narcolepsy Task Force confirms the tentative conclusion published in its Interim Report last January that the Pandemrix vaccine used in the winter of 2009–2010 contributed to the increased incidence of narcolepsy observed among 4–19-year-olds in Finland.
Association
Confirmed association with Pandemrix
Conclusion:
According to the report, the increased risk associated with vaccination amounted to six cases of narcolepsy per 100 000 persons vaccinated in the 4–19 age group during the eight months following vaccination. This was 12.7 times the risk of a person in the same age group who had not been vaccinated. No increased incidence of narcolepsy was observed among children under the age of four or among adults over the age of 19.
Limitations:
N/A
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Country/regulatory agency:
France
French Medicines Agency
AFSSAPS
Back ground:
The French data updated pharmacovigilance show 25 cases of narcolepsy reported in the 5.7 million people vaccinated with Pandemrix Panenza ® and ®, including 11 children aged under 16 years. The number of reported cases among vaccinated adolescents is slightly higher than expected number of cases in this age group. In overall analysis, the number of cases of narcolepsy observed after vaccination against influenza A (H1N1) is not higher than expected in the general population out vaccination
Each year, 900 new cases of narcolepsy are counted in France.
During the campaign of vaccination against pandemic influenza A (H1N1) that occurred between October 2009 and March 2010, about 5.7 million people were vaccinated in France, mainly Pandemrix ® and Panenza ®
Preliminary Reports
(Hyperlinked resources)
Pandémie de grippe A (H1N1)v : bilan de pharmacovigilance des vaccins (11/05/2010) *(102*ko)
Result of report:
The French data updated as part of enhanced monitoring of pharmacovigilance show 25 cases of narcolepsy (with cataplexy, 20) reported in people vaccinated Pandemrix ® (23 cases out of 4.1 million people vaccinated) and Panenza ® (2 cases out of 1.6 million people vaccinated) . In all cases, test results recording sleep confirmed the diagnosis of narcolepsy. The 25 cases of narcolepsy observed after vaccination occurred in 14 people aged 16 and older and 11 adolescents aged 8-15 years. The onset of symptoms occurred between 2 days and 5 months after vaccination. Risk factors (family history) may explain the occurrence of these adverse effects were found in 4 adult patients (multiple sclerosis, optic neuritis, cranial trauma and hypersomnia) and 2 adolescent patients (myasthenia gravis and narcolepsy)
These figures are lower than the number of cases of narcolepsy reported in the general population. However, the specific age group 10 to 15 years, the number of cases observed among vaccinated adolescents is higher than expected number of cases annually: 9 cases of narcolepsy reported in a population of 670 000 adolescents vaccinated with Pandemrix ® for 2.1 expected.
Association:
Weak temporal association
Conclusion
Weak link to temporal association in supporting vaccine over view
Limitations:
Absence of data on people who were not vaccinated, a reliable assessment on the possible link with the vaccine cannot be made
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Country/regulatory agency:
EMEA
CHMP assessment
Back ground:
Pandemrix, an (H1N1) v influenza vaccine, has been authorised since September 2009 and was used during the 2009 H1N1 influenza pandemic in at least 30.8 million Europeans.
As per 17 September 2010, there are 81 reports from healthcare professionals suggestive of narcolepsy, all collected through spontaneous reporting systems. Of these, 34 reports come from Sweden, 30 from Finland, 10 from France, 6 from Norway and 1 from Portugal. In addition, there are a further 13 consumer reports from Sweden and 2 from Norway. The age range of patients is between 4 and 52 years.
Preliminary Reports:
(Hyperlinked resources)
European Medicines Agency - News and press release archive - European Medicines Agency updates on the review of Pandemrix and reports of narcolepsy
http://www.ema.europa.eu/ema/index....nts.jsp&mid=WC0b01ac058004d5c1&jsenabled=true
23/09/2010
Result of report:
The ongoing review will require new observational (epidemiological) research in order to reach any firm conclusions on whether there is a link between Pandemrix and narcolepsy.
The Agency is in contact with its international regulatory partners (in the United States of America, Canada and Australia), to compare the available data with information from outside Europe. In addition, an investigation in collaboration with the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) is in progress. ECDC has presented a plan for an epidemiological study of narcolepsy and pandemic vaccines to be conducted by a network of research and public health institutions (VAESCO) in several EU Member States. The study protocol is currently being evaluated by the EMA.
Association:
Initial review only!
Conclusion
The ongoing review will require new observational (epidemiological) research in order to reach any firm conclusions on whether there is a link between Pandemrix and narcolepsy.
Limitations:
The ongoing review is complex and will take some three to six months to complete. (note not a limitation but overview)
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Country/regulatory agency:
EMEA
Back ground:
European Medicines Agency has launched a review of Pandemrix on the request of the European Commission to investigate whether there is a link between cases of narcolepsy and vaccination with Pandemrix. A limited number of cases was reported, all collected through spontaneous reporting systems, mainly in Sweden and Finland. Pandemrix, an influenza vaccine, has been used since September 2009 for vaccination against H1N1 influenza in at least 30.8 million Europeans.
Preliminary Reports:
(Hyperlinked resources)
European Medicines Agency starts review of Pandemrix (27/08/2010)
Result of report:
Although the cases of narcolepsy have been reported in temporal association with the use of Pandemrix, it is at present not known if the vaccine caused the disorder
Association:
Initial review ongoing
Conclusion:
Concluded that the available evidence was insufficient to determine whether there is any link between Pandemrix and reports of narcolepsy, and that further studies were necessary to fully understand this issue.
The Agency is also liaising with the European Centre for Disease Prevention and Control (ECDC), international regulatory partners and the World Health Organization (WHO).
Limitations:
N/A
_____________________________________________________________
Country/regulatory agency:
EMEA
CHMP assessment
Back ground:
The Committee concluded that the new evidence added to the concern arising from case reports in Finland and Sweden, but that the data were still insufficient to establish a causal relationship between Pandemrix and narcolepsy. Further analyses and study results are awaited to clarify the observations in Finland
Preliminary Reports:
(Hyperlinked resources)
European Medicines Agency reviews further data on narcolepsy and possible association with Pandemrix
18.02.2011
Result of report:
Committee reviewed the preliminary results of the Finnish study, an epidemiological study that compared the incidence of narcolepsy in people aged 4 to 19 years vaccinated with Pandemrix between 1 January 2009 and 31 December 2010 with the incidence of narcolepsy in unvaccinated people of the same age. The study, conducted by the Finnish National Institute for Health and Welfare (THL), suggested a nine-fold increase in risk of narcolepsy in the vaccinated population studied (an increase from approximately 1 to 9 cases per 100,000 vaccines), although the occurrence of narcolepsy was still very rare even with this apparent increase.
Association:
insufficient to establish a causal relationship between Pandemrix and narcolepsy
Conclusion:
insufficient to establish a causal relationship between Pandemrix and narcolepsy
Limitations:
Committee concluded that the THL study was well-designed, although it remains possible that unmeasured effects and biases could potentially have contributed to the observed increased risk. One possible explanation for the results is that Pandemrix may have interacted with an unknown local environmental and/or genetic factor in contributing to an increased risk of narcolepsy among those aged 4 to 19 years in Finland.
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Country/regulatory agency:
EMEA
CHMP assessment
Back ground:
The review of Pandemrix and the occurrence of cases of narcolepsy was initiated at the request of the European Commission under Article 20 of Regulation (EC) No 726/2004, on 27 August 2010, following an increased number of reports on narcolepsy in Finland and Sweden. Related press releases dated 27 August 2010, 23 September 2011 and 18 February 2011 are available on the Agency's website.
Preliminary Reports:
(Hyperlinked resources)
Result of report:
European Medicines Agency recommends interim measures for Pandemrix 15/04/2011
Association:
Inconclusive
Conclusion:
Interim measure pending the outcome of the European review in July 2011
Interim Label change by GSK pending further investigation
“When considering the use of Pandemrix in children and adolescents, an individual benefit risk assessment should be performed taking this information into account.”
Limitations:
N/A
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Country/regulatory agency:
WHO/Europe
Back ground:
Pandemrix® vaccine was used in 38 countries worldwide during the 2009/2011season. Increased cases of narcolepsy have been observed only in Finland, Iceland and Sweden.
WHO’s attention was first drawn to reports of narcolepsy following vaccination with Pandemrix® in Finland and Sweden in August 2010;
Preliminary Reports:
(Hyperlinked resources)
Pandemrix® vaccine and increased risk of narcolepsy
http://www.who.int/vaccine_safety/t...sessing/narcolepsy_february2011/en/index.html
01-02-2011
Result of report:
On the advice of the Finnish National Narcolepsy Task Force, the Institute concludes that vaccinated people aged 4–19 years had a risk of narcolepsy 9 times that of the unvaccinated. The Institute considers that the Pandemrix® vaccine was probably a contributing factor to this observed increase, but states that further investigation is needed of other significant co-factors associated with the increased risk of narcolepsy.
Association:
On the advice of the Finnish National Narcolepsy Task Force, the Institute concludes that vaccinated people aged 4–19 years had a risk of narcolepsy 9 times that of the unvaccinated. The Institute considers that the Pandemrix® vaccine was probably a contributing factor to this observed increase, but states that further investigation is needed of other significant co-factors associated with the increased risk of narcolepsy.
Conclusion:
Recommendations for the use of influenza vaccines for the 2010/2011 season in children and adolescents remain unchanged
Limitations:
N/A
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Country/regulatory agency:
Global Advisory Committee on Vaccine Safety (GACVS)
Press release
Back ground:
Since August 2010, following widespread use of vaccines against influenza (H1N1) 2009, cases of narcolepsy, especially in children and adolescents, have been reported from at least 12 countries. Narcolepsy is a rare sleep disorder that causes a person to fall asleep suddenly and unexpectedly. The rates reported from Sweden, Finland and Iceland have been notably higher than those from other countries. The National Institute for Health and Welfare of Finland issued a preliminary statement on 1 February 2011 following an investigation into the cases in Finland. A systematic retrospective registry-based review was conducted of all new narcolepsy cases diagnosed during 2006-2010 and cases in 2009-2010, born in 1990 or later, were reviewed using newly developed Brighton collaboration criteria for the disease. During 2009-2010 they found a higher risk of narcolepsy among those aged 4-19 years old who had received the vaccination against influenza (H1N1) 2009 compared with those who had not been vaccinated
Pandemrix vaccine was used in 47 countries worldwide during the 2009-2010 season
Preliminary Reports:
(Hyperlinked resources)
WHO Global Advisory Committee on Vaccine Safety recommends further investigations prior to drawing conclusions on the potential association between narcolepsy and pandemic influenza vaccines as communicated at WHO | Statement on narcolepsy and vaccination
http://www.who.int/vaccine_safety/t...sessing/narcolepsy_february2011/en/index.html
8 February 2011
Also see 21 April 2011 - Statement on narcolepsy and vaccination - update 2
Result of report:
The National Institute in Finland (on the advice of the Finnish National Narcolepsy Task Force) has concluded that the risk of developing narcolepsy among those vaccinated aged between 4 and 19 years is about nine times greater than those unvaccinated in the same age group, corresponding to a risk of about 1 case of narcolepsy per 12,000 vaccinated in this age group. The increased risk has not been seen in younger or older age groups. Narcolepsy is a condition that has a strong genetic linkage, being almost uniquely seen in persons who have the (HLA) DQB1*0602 genotype. Of the cases of narcolepsy tested so far in Finland (n=292), diagnosed during 2009-2010, all have that genotype
Association:
Inconclusive – monitoring continues
Conclusion:
WHO's Global Advisory Committee on Vaccine Safety (GACVS) reviewed this data by telephone conference on 4 February 2011. GACVS agrees that further investigation is warranted concerning narcolepsy and vaccination against influenza (H1N1) 2009 with Pandemrix and other pandemic H1N1 vaccines. An increased risk of narcolepsy has not been observed in association with the use of any vaccines whether against influenza or other diseases in the past
Limitations:
Awaiting further reports!
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Country/regulatory agency:
EMEA
CHMP assessment
Back ground:
The review of Pandemrix was initiated to investigate a possible link between Pandemrix vaccination and narcolepsy, following an increased number of reported cases of narcolepsy among children and adolescents in Finland and Sweden. The reported cases of narcolepsy occurred following the H1N1 pandemic vaccination campaign in late 2009 and early 2010. The current review has been conducted in the context of seasonal use.
Preliminary Reports:
(Hyperlinked resources)
European Medicines Agency recommends restricting use of Pandemrix 21/07/2011
Also see-
Questions and answers on the review of Pandemrix influenza vaccine (H1N1) (split virion, inactivated, adjuvanted) A/California/7/2009 (H1N1)v like strain (X-179A) 21/07/2011
Jul 21 GSK statement
Result of report:
The CHMP considered that the epidemiological studies relating to Pandemrix in Finland and Sweden were well designed and the results show an association between Pandemrix vaccination and narcolepsy*in children and adolescents in those countries. The results indicate a six- to 13-fold increased risk of narcolepsy with or without cataplexy in vaccinated as compared with unvaccinated children and adolescents, corresponding to about an additional three to seven cases in every 100,000 vaccinated subjects. This risk increase has not been found in adults (older than 20 years). A similar risk has not been confirmed but cannot be ruled out in other countries.
Association:
Preliminary (Strong signal in Finland) Risk vs. benefit remains positive
The CHMP noted that similar epidemiological studies have not been completed in other countries. The preliminary results of the VAESCO study confirmed the signal in Finland. Results are still preliminary and do not allow conclusions in other countries (where vaccination coverage with Pandemrix was lower), but the final results of the VAESCO study are still awaited.
The marketing authorisation holder for Pandemrix, GlaxoSmithKline, is carrying out a retrospective cohort study in Canada, where an equivalent H1N1 vaccine (Arepanrix) was widely used. The company is required to carry out non-clinical and clinical studies in order to further explore the association between Pandemrix vaccination and narcolepsy
Conclusion:
The CHMP recommended that the product information for Pandemrix should be updated to state that in persons under 20 years of age, Pandemrix should only be used if the recommended seasonal trivalent influenza vaccine is not available, and if immunisation against H1N1 is still needed, for example, in persons at risk of the complications of infection. This revision does not apply to adults over 20 years of age.
Limitations:
N/A
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Need further updating for the rest:
1. VAESCO (July 11 2011)
The preliminary findings of the VAESCO study confirmed a signal in Finland, but do not enable conclusions to be drawn in other countries, where vaccination coverage with Pandemrix was lower
2. Canadian study
Glaxo Smith Kline(GSK) 9July 11 2011)
3.
4. WHO 2013:
GACVS reviewed 2 safety updates on influenza A(H1N1) pdm09 vaccines, which included associations with narcolepsy and with GBS. The association between use of the adjuvanted pandemic vaccine Pandemrix® (Glaxo-
SmithKline) and abrupt juvenile narcolepsy has thus far been confirmed in 4 countries (Finland, Ireland, Norway and Sweden)
Global Advisory Committee on Vaccine Safety, December 2012
Relative risk was significantly
raised, ranging from 6.6 (95% confidence interval [CI]:
3.1–14.5) in Sweden to 13.0 per 100 000 (95% CI: 4.8–
34.7) in Ireland
Most cases of narcolepsy,
with or without exposure to Pandemrix®, occur
in subjects who carry the HLA DQB1*0602 allele. The
importance of understanding the triggers and causes of
this association will be crucial
GACVS considered that research should continue to better
characterize the possible underlying biological
mechanisms of this association.
Additional studies are being finalized in the United Kingdom (UK) and Canada
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The information here is my research alone and no conflict of interest noted!
EXCEL spreadsheet/linelist
-The tentative diagnostic criteria of narcolepsy according to the Brighton collaboration and theEuropean Narcolepsy Network
Level 1 of diagnostic certainty
In the presence of:
criterion 1: Excessive daytime sleepinessa and/or suspected cataplexy
AND
criterion 2: CSF hypocretin-1 deficiencyc
Level 2 of diagnostic certainty
In the presence of:
criterion 1: Excessive daytime sleepinessa
AND
criterion 2: Definite cataplexyb
AND
criterion 3: Level 1 or 2 MSLT abormalitiesd
Note: criterion 3 has only been added to add some form of ‘objectivity’ (without sacrificing sensitivity)
Level 3 of diagnostic certainty
In the presence of:
criterion 1: Excessive daytime sleepinessa
AND
criterion 2: Level 1 MSLT abnormalitiesd
In the absence of:
criterion a: Other mimicking disorders, see
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Case definition:
----
The tentative diagnostic criteria of narcolepsy according to the Brighton collaboration and theEuropean Narcolepsy Network:
A. Excessive Daytime Sleepiness
Definition in adults (>= 16 years):
An acquired condition, characterized by:
-involuntary sleep episodes during the day
-present almost daily for at least one month
Definition in children (< 16 years):
An acquired condition, characterized by:
-clear increase in daytime sleep episodes
-usually in combination with feelings of subjective sleepiness and impaired concentration
-present almost daily for at least one month
B. Definite cataplexy
definition in adults (>= 16 years):
Presence of all of the following criteria (before initiation of treatment):
-episodes of muscle weakness
-with preserved consciousness
-at least 2 attacks with a clear trigger
-majority of attacks lasting < 30 seconds
Episode with documented reversible areflexia will also qualify as definite cataplexy, regardless of the above
criteria.
Definition in children (< 16 years):
Children may present with cataplectic episodes that fulfill the criteria for adult cataplexy.
There may also be another phenotype that is restricted to children, with the following criteria:
-Acute-onset movement disorder, characterized by
-Falls to the ground (i.e. while walking or running), and/or
-Generalized hypotonia, and/or
-Head drops and/or
-Prominent facial involvement resulting in “cataplectic facies”, with ptosis, mouth opening,
tongue protrusion, remarkable facial weakness, grimaces.
-Preserved consciousness
-Triggered by possible ‘emotional’ circumstances, such as when watching funny cartoons, eating
certain food, playing games.
-Emotional triggers can be absent in the first weeks after onset
-Duration of a few seconds to several minutes, but often present in protracted clusters due to
continuing emotional triggers
-Episodes can be clearly distinguished from epileptic seizures or neuromuscular disorder
C. Hypocretin-1 deficiency
Hypocretin-1 concentration below 110 pg/ml using the Phoenix radioimmunoassay in crude, unextracted CSF. Performed in a laboratory according to published guidelines, using the Stanford reference sample.1
1 Lin et al. Guidelines for the appropriate use of CSF measurements to diagnoste narcolepsy and accrediation of measurement sites. In: Narcolepsy and Hypersomnia, 1st edition, 2006. Edited by Bassetti, Billiard and Mignot.
D. Multiple Sleep Latency Test Criteria
4 or 5 nap MSLT performed according to the AASM protocol2
A. Mean sleep latency of less than 8 minutes (adults) or less than 12 minutes (children <16 years) 3,4
B. At least 2 sleep-onset REM periods
Level 1: A AND B
Level 2: A OR B
Note: “level 2 MSLT” has only been added to have a certain form of ‘objectivity’ without sacrificing sensitivity.
e To be excluded
The following conditions should be excluded:
Source: The interim report from the Finnish National Institute for Health and Welfare study can be found on its website:
http://www.thl.fi/thlclient/pdfs/dce182fb-651e-48a1-b018-3f774d6d1875
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Other sleep disorders, according to ICSD-2 criteria:
Sleep disordered breathing
Behaviorally Induced Insufficient Sleep
Circadian Rhythm Disorders
Recurrent hypersomnias
Hypersomnias secondary to medical or psychiatric conditions
Use of sedating medication
Focal cerebral lesions, indicated by neurological examination and/or brain imaging
-----------
Narcolepsy with cataplexy diagnostic criteria (Am Academy of Sleep Med)
Narcolepsy with cataplexy diagnostic criteria (Am Academy of Sleep Med)
Excessive daytime sleepiness occurring almost daily for at least 3 months.
Definite history of cataplexy, defined as sudden and transient (less than 2 minutes) episodes of loss of muscle tone, generally bilateral, trigged by emotions (usually laughing and joking).
Diagnosis should, whenever possible, be confirmed by nocturnal polysomnography (with a minimum of 6 h sleep) followed by a daytime MSLT:
Mean daytime sleep latency 8 minutes or shorter, with two or more sleep onset in REM periods (the time from sleep onset to REM sleep should be less than 15 minutes in at least two naps).
Alternatively, hypocretin‐1 concentrations in the cerebrospinal fluid 110 pg/ml or lower, or a third of mean control values.
The hypersomnia is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder.
-------------------------------
The importance of genetic factors:
HLA (human leukocyte antigen) DQB1*0602 allele
Ninety five percent of Caucasian and Asian patients with narcolepsy carry the same genetic factor, the so-called HLA (human leukocyte antigen) DQB1*0602 allele.
This HLA class II allele is responsible for presenting antigenic structures to the so-called CD4, or helper T-lymphocytes, and thus this allele regulates the activity of white blood cells. This genetic factor is found in approximately 28% of Finnish children.
Its prevalence varies in the European population from 4 to 28%.
In the Northern European populations (Finland, Sweden, England, Germany), genetic risk of narcolepsy can be found in approximately 25–28% of the population
Southern Europe (Greece, Italy, Slovenia), the genetic risk occurs in 4–13% of the population.
HLA (human leukocyte antigen) HLA DQB1*0603 allele
The HLA DQB1*0603 allele, on the other hand, seems to protect from narcolepsy. The distribution of this protective allele is very similar to the distribution of the predisposing allele, i.e. the highest prevalence is found among North Europeans (7-8%) and lowest in Southern Europeans (1-4%)
(Thus, the narcolepsy related HLA genotypes are very similar in the Northern European countries; the prevalence of DQB1*0602 HLA-risk genotype or HLA DQB1*0603-protective factor cannot explain the emergence of narcolepsy associated with Pandemrix vaccination in Finnish children!)
Because of this very strong association with the genetic risk factor which regulates immune responses, narcolepsy is considered an immune-mediated disease.
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