so hello everybody my name is Ramy Katami i welcome you to my lecture um my topic is I going to talk about how vigilance is assessed uh with a focus on the objective tests which is MWT MSLT and other vigilance tests so when talking about vigilance in the context of sleep and sleep medicine we frequently talk about the impaired vigilance which is sleepiness or excessive daytime sleepiness um and therefore in the next slide I show you my goals of the talk so I'm talking about sleepiness and excessive daytime sleepiness and the first thing I'd like you to learn is that there are different dimensions of sleepiness so this is important sleepiness is not a uni-dimensional construct but there are different dimensions to consider when assessing and treating sleepiness so for example there is an ability to fall asleep but also the ability to stay awake so this is something we have to to consider and to discuss next I'd like you to learn is that these difference dimensions is reflected subjectively and at objectively levels so again we have to consider then and this automatically implies that I want you to learn how to assess subjective sleepiness for example by history taking or using scales on scores but also to learn how to perform and how to interpret objective vigilance tests so let's start and have a closer look what I said uh there are multiple dimensions of sleepiness um the most prominent one and this is also what is the most cumbersome for subjects and patients is the difficulty staying awake um this is reported by the patients and this is also sometimes observable sometimes they fall into sleep even in talking to you so difficulty staying awake means that there is an increase and sometimes involuntary daytime napping and this is something you have to record another aspect is less obvious but very cumbersome for the patient this is the difficulty with sustained attention because this is frequently associated with cognitive and emotional dysfunction the ne next aspect written here listed here is the increased need for sleep this is a slightly different aspect because it's not qualitatively aspect but it's a quantification of sleep and here by definition we say that if somebody needs more than 11 hours per 20 hours sleep then we say it's a hyperomnia hypers lens um there are three additional features written down here and these are equally important but they are somehow neglected therefore I want to emphasize them a little bit what is frequently neglected is automatic behavior what is automatic behavior automatic behavior refers to behavior this is semi-purposeful or even nonsense behavior and which is again somehow involuntary even not recordable by the by the patients so for example um automatic behavior which can be very very complex is for example putting clothes in the dishing machine or vice versa put a dish in the washing machine but I've also experienced patient driving for hours with automatic behavior so it's very complex and even for different differential diagnostic challenges for example differentiating this from complex behavior um in epilepsy um there's also a difficulty to wake up for some patients uh which can be enhanced by sleep drunkenness and putting these three together um the reason why I did this is that we don't have very good assessment tests so we don't have objective tests to measure this and therefore it's very important to make a very good clinical history and a very good clinical interview to assess them okay let's let's continue with definitions um the the definition of excessive daytime sleepiness first uh sleepiness sleepiness is something we all know this is a physiological phenomenon um everybody knows that if we stay up a long time we will get sleepy there's also circadian modulation um and we are prone to sleepiness between 200 a.m and 6:00 a.m but usually it depends on the time we stay awake um contrary excessive daytime sleepiness and I alluded this is the inability to stay awake um presented as falling asleep and this is now very important even in inadequate situations or in situations that interfere with performance of daily life this can be let's say normal situations you all know in a meeting that you fall asleep um and if you do this repeatedly then it's excessive daytime sleepiness but it also can happen during driving and then it becomes very obvious why this definition is so important it's frequently improved by sleep um but not exclusively but this is very characteristic so don't forget to ask this we have to differentiate this against fatigue um I will come to this in a second also against depression and apathy and hyperomnia this is already what I what I mentioned this is more a quantitative differentiation um so in clinical terms how does excessive daytime sleepiness present well it's the tendency to fall asleep this is what I I mentioned now several times this is something you have to ask or observe during the interview uh it can present a sleep attack so involuntary and abrupt um don't forget to ask uh um for automatic behavior and don't forget to ask that there is a possibility for the subjects to distract sleepiness and this is usually activity usually motor activity maybe you know this by yourself also when you get sleeping you stand up walking around and then transiently for a few minutes or longer you can resist sleepiness so this is very very typically never ask uh never forget to ask about traffic accidents excessive daytime sleepiness is related to a very high risk of traffic accidents um there are also unspecific features um so sleepiness excessive daytime sleepiness is frequently accompanied by sleep disorders not necessarily but frequently so it's worth to ask for it it's associated with associated with cognitive dis function and um also with psychosocial psychological problems okay um let's go next to the definition of fatigue and this is an important thing to distinguish excessive daytime sleepiness and fatigue also in clingal terms but um but in addition in petrophysiological terms fatigue is much more complex fatigue refers to a physiological and psychological tiredness so it again it has several levels we can define these levels it's on a cognitive emotionally and bodily level so really quite complex and to have a first approach to this you can you can note that usually fatigue is not improved by sleep this is clearly opposite to sleepiness fatigue has to be differentiated against excessive daytime sleepiness muscle weakness which is not so easy so never overlook as a clinician never overlook um a muscle disease because you think this patient is just fatigued also against depression and apathy which is also not so easy in single cases and motivation which is again complex so you see fatigue is quite a complex construct and not easy to deal what is the clinical approach well the clinical approach helps you a lot um strong tiredness and this is what the patient report subjective feeling of strong tiredness is following normal activities so as an example um a fatigue uh subject uh will report that half an hour housekeeping will exhaust him a lot and he needs a long and a prolonged need for recovery maybe hours to recover so this is very very typical for fatigue usually it's not improved by sleep i mentioned it and usually it's not distracted by motor activity again opposed to excessive daytime sleepiness uh on the contrary fatigue patients tell you that motor activity aggravates their fatigue again there are unspecific features frequently uh some kind of pain for example headache or muscle pain then increased rest time this is also something we can measure this is the only thing we can really objectively measure in fatigue cognitive dysfunction and many times and my impression is even worse than in excessive daytime sleepiness psychosocial problems the definition of hyperomnia and then we are we are done with the with the definitions um this is somehow easy i've already mentioned that is it's a quantitative definition it's an increased of sleep duration more than 11 hours per 24 hours um and this is something we can also objectively measure um let's go to the operative assessment of sleepiness and disturbed sleepiness um we frequently use scales and scores and this is the mo the most widely distributed and most famous one this is the app sleepiness scale it's a very easy and easily applicable scale um it ask for eight situations just like sitting and reading and the probability the chance of dozing off zero is you would never dose off and three is there is a high chance of dozing off so again very subjectively it's filled out by the patient um if you read this um you see there are passive situations watching television this is not very active but we are also asking for for active situations for example um sitting and talking to someone so both situations are covered and then you easily sum up the score and you have a sum score and the next slide shows you uh what you can expect um so this is the mean scores the sum of the score and this is for different um disorders here you see up to 10 points it's normal then there is an abnormal range and there severe range up here you see the most severe one are in idiopathic hyperomnia or for example narcolepsy you see also obstructive sleep apnoa patients can be very very uh sleepy um but you see there's also a broad range the same is in PLM disorder and usually in insomnia the sleepiness scale is quite low there's a similar scale in the fatigue um area in the fatigue domain this is called fatigue severe scale there are many others we use this because it's well standardized it's translated in different countries languages and it's widely distributed and validated in different countries it's quite similar we are asking nine pat nine questions here to the patients the range is a little bit more broad so um the the values range from one to seven they are summed up and then divided by nine to get the mean score and the cutoff is four okay having talked about this um I come to my first question um so you can see if you if you got the main messages the key messages i show you this young guy here um and assume he is sleepy at least I assume this and I would ask you is this guy fatigue is this hyperomnia or is this excessive daytime sleepiness and in the picture you see some keys one thing it's not dark so it's during daytime it's quite bright obviously this lady has an umbrella maybe for the sun maybe for the Um and the position of the guy especially his head is not very physiologic it's more like a flying dog they sleep like this but not humans so the right answer would be excessive daytime sleepiness why because increased sleepiness even in inadequate situations um there's also another cartoon this is one of my favorite definitions of narcolepsy so if you fall asleep in front of the television when watching TV in the evening this is not narcolepsy this can be normal depending on your day you're probably quite sleepy and if the TV is boring you fall asleep if the lady the TV lady falls asleep in front of you then definitely this lady has narcolepsy she's very daytime excessive sleepiness okay let's come to um the objective measures and what I put here together is what is the construct of an ideal objective vigilance test um there are several points to consider the first point is and this is definitely the most important one an objective measure should be capable in measuring these specific dimensions of sleepiness this is what I introduced to you we have different dimensions of sleepiness and of course we want to have tests that can cover and measure these so we need different tests to reflect also the patients need uh meet the patients complaints so in this sense it should be specific and this is also what I put here in the figure on the top a test should be quite specific next is it should distinguish normal from pathological sleepiness um because this is a range I also uh introduced this uh sleepiness is a normal phenomenon excessive daytime sleepiness is pathological so a test should be able to distinguish sleepiness excessive daytime sleepiness caused by disease or caused by insufficient sleep so if we sleep less and we do the test it should tell us okay this is normal sleepiness so in this sense it should be diagnostic i put this here on the right side a test should also be able to assess the severity of sleepiness because for diagnostic and for treatment p purpose we want to see the changes of sleepiness so in this sense it should be scalable and sensitive and what's equally important is written down here a test should be broadly available and accessible and it should be quick and easy and to apply and this is somehow a little bit a problem of established tests they are not so easy to apply but I show you this in a second okay what you what what what you see here this is a table and I list the tests here what I'm going to talk about um their dimensions what they measure and the metrics they use um there are many more tests of course but these are the most frequently used ones and these are the most important ones so I focus on this um let's first refer to MSLT and MWT they measure the ability or the drive to fall asleep some people also say MSLT measures sleep ability the MWT the ability to stay awake and they both use sleep latency as a metrics the MSLT in addition uses sleep stages so in this sense this is the only test which is also diagnostic um the PBT and the SARD you will see these are not electrphysiological tests like the MSLT and the MWT but they are based on behavioral tests so they are using speed and occurrency to measure sustain attention both of them where the SAR has additional functions reflecting this is decision making and motor inhibition and finally um but this will be very quick um I mentioned that hyperomnia the increased need of sleep should al also be objectively reflected and we can do this by long-term recording of the PSG or better the acttography um what's very important for a test besides specificity is sensitivity so we want to have tests that are sensitive enough um and this is a very nice composition of many many tests you see the list is much longer than my table um and how sensitive or less sensitive these tests are so this is a ranking of the tests here on the top are listed the most sensitive and at the bottom here are the least sensitives and these is the excess this is expressed as the effect size so what you can easily recognize is that the latency tests the sleep latency tests and the latency to sleep are the most sensitive one with quite strong effect sizes also the psycho motors or the performance tests they're also sensitive and this is one of the reasons I choose them and I think this is one of the reasons why these tests are so widely distributed throughout uh the countries okay let's start and this is the first test I go into details with the multiple sleep latency test so again I mentioned is it measures the ability to fall asleep it does it quantitatively by measuring latency but also qualitatively by assessing sorm sleep episodes i will allude to this later in a second so in this sense the MSLT um is not very specific but it's quite diagnostic the MSLT is the only test which can be diagnostic for one disorder and this is the narcolepsy um it's well established uh introduced uh in the 70s standardized several times uh it's well validated by sleep deprivation but also the opposite of extending sleep um also tested for sedating and vague promoting drugs and their effects so we know that it's quite good scalable and sensitive in measuring this it's also highly reliable uh we have a high intraator and a high interrator relability and a very good test retest railability um unfortunately and this is the drawback of the tests they are not easily and quickly apply um you need a sleep lab you need people doing this and you need the whole day to perform them so the availability is restricted and limited and it's definitely not a test easy and quickly to apply this is how it works um so we are using EG electrodes EOG electrodes and EMG re electrodes to measure the sleep latency during the day so we do this and this is shown here five or five four or five times a day for 20 minutes each nap here and the interval between the naps is 1.5 to two hours um the patient or the subject is lying in bed um and the MSLT must be performed immediately after PSG so um doing an an MSLT without PSG does not make sense because um you must know how sleep was before measuring sleepiness and as I told you it's not very specific um also normal subjects or patients um can be sleepy because they have a poor poor poor sleep the night before so you must record this and the recommendation is that you must record at least 6 hours of normal sleep the first test should be uh started um 1.5 hours to 3 hours after awakening and these are the conditions this is in detail but it's very important to know the rooms of course should be dark and quiet um you have to remove mobile fines uh phones temperature should be comfortable for the patient because it influences sleepiness you have to stop medication especially stimulants and some uh RAM suppressing medications at least two weeks before MSLT this is important otherwise you're measuring um a pharmacological effect but not sleepiness prone to the patient smoking should be stopped at least 30 minutes before each nap and the patient on the subject should refrain from from caffeine in or you record how many coffee in they have have taken before in between the tests so in between the intervals here strong physical activity and bright light should be avoided this also influences the test result um this is how the recording works um 20 minutes um should be recorded this is a fixed time for each test so for each of these five or four naps but if sleep occurs within 20 minutes you have to prolong this for another 15 minutes just to make sure that when patients fall asleep um you capture a potential sorm episode the measures you you get is mean sleep latency expressed in minutes of all these five or four naps the number of sorm sleep episodes and the mean latency to REM sleep there are three factors influencing the MSLT results um definitely one is if you record four naps or five naps the normative value for four naps is 10 minutes roughly roughly speaking 10 minutes five nets roughly speaking 12 minutes so this is important to know you see that there is a quite variation and this is also the problem of the test and the problem the normative values that statistically speaking it's not very from the statistical construct it's not very very sound um another factoring factor influencing the result is the latency definition there are studies out that if you only consider the first sleep stage or sustained sleep so two or three sleep stages in a row their differences up to two minutes and the most important influencement factor is age and this is also shown here the mean latency as a function of age tells you that mean latency in higher ages is increasing here up to in the very elderly patients up to 15 minutes um this is a summary this is a very nice study showing what you can expect from the latency in a population study this is a mixed population clinical so patients and also healthy subjects um down here you see uh this is the latency up to 20 minutes and this is the frequency so how frequent um the latency occur and you can see here you're not sleepy if you're 10 hours for two weeks in bed or eight hours uh for for five nights you get latencies between 10 and 20 minutes which is the normal range if you're 6 hours in bed for four nights you get a moderate sleepiness which is here if you're an a resident uh an anesthesia resident here so if you're on night shift or night duty you get a sleep latency of five which um is equival equivalent um to a patient with se severe sleep apnnea syndrome and if you don't sleep a night at all you are similar in the range as narcolepsy between two and three minutes um these are um the MSLT results in disease um I told you it's widely used um but still there are controversies about this test especially the latencies in narcolepsy for example it has been changed several times now in the new classification the mean latency is lower equal or lower 8 minutes but look at the the history it has been changed several times from 3 minutes to five minutes so still this is the the chapter is not closed there are still discussions on it um and this is because um uh the I I alluded to this the statistical contract construct is not is not sound for for deviations and um um variability um here you can see that the test is quite sensitive to changes uh for example modapheneal and material phenidate um changes um the mean latency quite robustly and repetitively also it has been applied in OSAS patients before and after CPAP and you can see the increased of the latency this is normalized in this studies but in most other studies and again the same point the changes remain within one one standard deviation which again points to the same problem that the statistical contra construct is not is not very clear um it has been also and this was a topic in the last couple of years it has been also challenged how specific the sorium sleep episodes are um this has been raised by several authored and conf authors and confirmed in several authors in narcolepsy so for type one and type two narcolepsy that it's not very repro reproducible if you do the test a second time um you don't see the sorm criteria any longer and in half of the patients you would have changed the diagnosis so there's a ongoing discussion on this and also and this has been shown previously before more than 20 years ago that also in normal subjects two sorms can occur in up to 17 patients uh in 17 subjects without complaining any sleepiness or other features of of narlepsy you can increase specificity uh this should be not a big topic here but combining the sorum sleep episode criteria with the sleep latency um in different combinations or also considering a sororum that occur during PSG at night you can increase specificity specificity quite high um I think more important and this is my observation when when also when when when I have carefully um looks in other labs is that sorum is often missed because it's false negative again and I want to emphasize this a single test is not closed and not ended after 20 minutes but it can last up to um 35 minutes to capture the sorum the sorm is also age dependent this is what you see here this is the latency and the number of sorms as a function of age and you see young patients young narcolepsy patients tend to have more sorms and this is decreasing with increasing age the next test I go in detail is the maintenance of wakefulness tests this is somehow similar but also different um again you test sleepiness but another dimension of sleepiness you measure the dimension of ability to stay awake during the day again in different sessions usually you do four sessions again at a 2hour interval the sessions are longer not 20 minutes but 40 minutes and again you start 1.5 or 3 hours after awakening this time the patient or the subject is not lying in bed but he's sitting and you have to care that he's comfortably sit sitting um and that there is no outside lightning because this can influence the test quite quite robustly quite profoundly and again look for the room temperature which should be co uh um comfortable for the patient because warm temperature this is probably your own experience can make you very sleepy the instruction is very important the in instruction is and um in my lab um the technicians had to read this from a paper because it's so important please sit still and remain awake for as long as possible look direct ahead of you do not look directly at the light i tell you later why this is so important and you have to survey the patients so it's not allowed to do counter activities to prevent sleepiness such as haychecking slapping singing i I have seen all these um counter measurements um done by the patient to prevent that they fall asleep so one one session is ended after 40 minutes if no sleep occure or earlier if sleep occure um it's a little bit different as the MSLT um if you use stage one you have to record at least three consecutive epochs of stage one or one epoch of any other sleep stage so two three or ram sleep then one epoch is enough um and the onset of sleep is again a mean latency of all these four naps um this is the characteristic and the profile of the test um I already mentioned it's the ability tests the ability to remain awake it's a quantitative test so the latency is uh the quantitative metrics frequently used in studies and also in everyday performance to measure therapeutic uh effects by medication or by other treatments but it's not a qualitative test so it's not diagnostic it's not like the MSLT that you can use the SORMS to make a diagnosis of narcolepsy um contrary to the MSLT we have normative values there is this study um and again it's not so easy again it's problematic um so the normative value in this healthy subject is uh roughly 30 minutes um the vast majority so 75 patients could stay awake 40 minutes so if I try to calculate this down to the uh fifth percentile fifth percentile then I come to the the value of 11 minutes and it was recognized in the clinical context this is not a good cutoff value because in narcolepsy the mean is um 12 minutes so then by yeah convention uh and agreement the uh 15% time was chosen which is 22.5 minutes again the problem is also it's a quite sensitive test it's very good scalable um it's not easy and not quickly to apply you have seen this uh and it's not available uh throughout all all labs um also probably it's much more influenced than other tests by motivation um there is a very nice study that has been done by by a Spanish group offering them a subjects a thousand euros to perform the test gives much better results so this also shows you that motivation is very very influential in this test and this is in important in the context of driving ability because we frequently assess the driving ability um by the MWT it's also strongly influenced by the instruction this is the reason why I said uh at least in my lab the technicians have to read this literally so in the 20 minutes version it can make up to five minutes or in the 40 minute version which is the usual one up to um 10 minutes differences depending on how you exactly instruct the patients also influenced by the position um again quite an impressive range up to seven minutes uh difference between sitting and lying and again it's age dependent this is similar to the MSLT showing you here the mean latency as a function of age um tells you that elderly patients have a higher latency next test I introduce are the performance tests um I think the most widely distributed is the psychoto vigilance test PVT um it's not electrphysiological test but it's based on behavior on performance it's a simple reaction time test so you measure motor response to a visual stimuli the visual stimuli is displayed here this is a counting number that pops up um which is irregularly popping up and you have to press as fast as possible um when the number occurs so this needs sustained attention and because the test is 10 minutes the stained attention is tested uh for 10 minutes so it's it's a shortterm sustained attention test um it's a quantitative test measured by speed and accuracy um there are various variables out there mean variability lapses omissions than the 10 fastest or the 10 slowest and each of the parameters are slightly different in in in their meaning errors of commission are also important um it's relatively specific but it's not diagnostic so un again opposed to the MSLT you cannot perform an MSLT and say okay this is this and this sleep disorder definitely not but the big advantage and this is shown here in the profile compared to the MWT in blue i did the profile for the um PVT in red is that it's quickly and easy apply and the availability is is much higher because it's a small device and you can apply this uh very easily it's quite sensitive and tested to sleep deprivation in healthy subjects it's tested again caffeine bright light work schedule and medications so it's definitely sensitive and scalable and again it's age dependent um here it is shown this was uh quite an impressive study um more than than 15 years ago now that it's quite sensitive against sleep deprivation also against chronic sleep deprivation which which is more um cumbersome to assess for us here you see the PVT lapses lapsis is a reaction time over 500 milliseconds across days of sleep deprivation so up to two weeks this is the control group being in bed for eight hours this is the chronic sleep deprivation group for 6 hours for 4 hours compared to a group with complete and total sleep deprivation over three days so quite a tough st uh study and what you see is that the lapses increase in the six-hour and the 4hour groups up to the values of 48 or even 72 hours um compared to the to the in the sleep total sleep deprived group so um chronic sleep deprivation is indeed a big problem um here in the baseline group you see there is also increasing naps slightly increasing and this is the reason why many people also say it does not only measure and not sensitive to sleep deprivation it also measures motivation and um many people say okay this baseline should be subtracted from the real values um here you see uh the the studies of age dependency um this is a sleep deprivation study uh made for 40 hours in young and in elderly uh subjects these are healthy subjects the dark one are the the the elderly one and what you see that the lapses again reaction times over 500 milliseconds or the variability of the test is much more robust over sleep deprivation in the elderly compared to the young people um it may and this is interesting um also for research purpose but maybe also for clinical purpose it may differ between sleepiness caused by homeostatic and circadian cicadium mediated sleepiness um obviously the variability and the 19% of slowest responses and the variability here is more sensitive here to sleep deprivation than um the 10 fastest percent so which essentially mean if you if you are doing the test and only looking at the 10 fastest response every subject is able to press very quickly um and perform this but the variability and the 90 slowest um percents are more sensitive to sleep deprivation it has been also tested against um in in patients with sleep apnnea syndrome and it state but there are few studies out that occurrency is more important than speed in these patients um but usually this is not not done in in clinical routine so I'm coming to my last test uh and this is the say sustained attention to response task the SARD this is also a test a performance test measuring sustained attention it's different to the PVT because the design is a go and no go design so what it essentially does is on a computer screen um they will pop up a number and you have to respond to a num to the number as fast and as accurate as possible press a certain button um and this is true for every number except the three if the three occurs you have to refrain from pressing uh the button and what it measures is um error rates so commissions and omissions there are other parameters out um maybe they're interesting for certain questions um so um including inhibition and including also decision making because you have to decide to press or not it's more than a vigilance test but the construct is that excessive daytime sleepiness will impair frontal function because decision making making and in inhibition is also a frontal function and therefore it's justified to use this test um we have not very much data on sensitivity so we don't know how this test these parameters and which parameter react to medication or other treatment so this is a little bit of problem we don't uh also know um how age dependent this test is the big advantage again is compared to MSLT and MWT um again it's another dimension and it's easy and quickly to apply and it's widely available because it's just it's just a software um it has been applied to disease um there were no differences when comparing narcolepsy type one and two against idiopathic hyperomnia and patients with OSAS so these are the error rates and you see there were no statistical differences they were different against the normal controls but not helpful in differentiating those so these test this test is not diagnostic and not very specific there was no correlation and to MSLT latencies again confirming that this is another dimension so definitely worse to include this test in your in your test battery um maybe there is a correlation from certain tests but um this has to be confirmed so these are my last slides um very quickly um um we have talked about about hyperomnia so the need to sleep more than 11 hours how can we objectively measure this um of course we could use polyomnography but this is not very senseful does not make much sense because of the high costs and it's uh there is there's no option to really do long-term monitoring over several days or even weeks so act is much better ecttoraphy is based on motion recording so these are like watches um worn on the wrist the non-dominant hand um and the big advantage is the multi-day recording um over several weeks or even months and you get a a a print out like this these are the days and here is the time information and usually there are two informations in there this is activity so the bars here which melting to a black pattern here telling you that this patient at that time was quite active um so we can assume that this patient is awake it's just an approximation but it's it's a very nice approximation and here between um um high noon and 6:00 in the morning we don't see much activity so we can assume that this subject um slept during this time and therefore it it's very easy and usually it comes together with a with a diary and to document hyperomnia in this way seeing that this patient has rest times uh more than 12 or 14 hours and sometimes it's a very easy uh um approach to differentiate for example from from those patient um who have um a Saturday night uh um u celebration or party syndrome so every uh Saturday this young patient went out and was sleepy and claimed to be hyperomnic which is uh after this very very easy testing which is not which was not true so I'm coming to the summary um I I've showed you that um we have subjective and objective levels of sleepiness um we have to assess this um because we have different dimensions of sleepiness um at a subjective level we use self-report and carefully history taking scales and scores at an objective level I've introduced these tests that are measuring sleep latency or are based on performance tests um I've not mentioned um but this is um important to know that there is a poor correlation between the subjective and the objective sleepiness just telling you that these are really independent levels that need to be assessed independently both are equally important for us and for the patient um I've introduced the objective tests in terms of sensitivity specificity scalability availability and how easy they are apply and how adequate are there for daily situations for example acttoigraphy or if we test um the ability to drive which is the MWT in the future and this is what we more and more recognize is that probably one parameter is not enough and what we have to do is more assessing a profile of sleepiness with the different dimensions and also monitor them over a long time so my my guess is that in future we will work more and more with compositive index with compositive scales uh with multiple markers and features reflecting the profile of sleepiness and this is what we definitely need also um to extend to subjective sleepiness so thank you for attention