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00:00:01
it's kind introduction and for having me it's great great pleasure to be here with one of these uh has also
00:00:07
they can s. rounded will be working up some fantastic place you're very lucky you or
00:00:13
so i will talk to you a little bit about um some technical aspects of it i didn't have a lot that the
00:00:20
uh i'm concentrating a little bit on diagnosis and differential diagnosis i'm
00:00:25
very lucky because i work in a place where we have a
00:00:29
the easy um each each clinic which
00:00:31
is concentrated mostly and differential diagnosis in use
00:00:35
electric of photography of output ten shows we have a dedicated your psychology so it's a bit of or
00:00:42
um meet environment between guests weren't already knew robert g. and um i'll finish off for tell you
00:00:48
a little bit about um sleep wake abnormalities which is being an interest of mine for a long time
00:00:55
um so um why should we be i'm really
00:01:00
dealing with the paladin calf up this this clinically relevant
00:01:04
um i'll show you some local data from our region this is uh
00:01:09
um surveyed that a colleague of mine doctor the
00:01:12
basket you did on sixty thousand litter related hospital visitation
00:01:17
in the event the region which is in the was still the telly between two thousand and six and two thousand eight
00:01:24
and it i think i forgot that it was the third corps of first the admissions
00:01:30
and it was the first calls of really it much so it is a relevant clinical pop
00:01:39
it affects a patient's ability um to go
00:01:42
about performing some of their daily tasks and
00:01:47
when i uh that that the teacher uh has concentrated on is driving
00:01:53
uh this is probably one of the best done a study is um
00:01:59
about a padding careful operating in driving in
00:02:02
germany where we go uh like driving test performed
00:02:06
and patients with varying degree oven careful up but you
00:02:09
were shown a have defects in many aspects expression integration
00:02:14
and one very peculiar finding that the study was that
00:02:19
both patients with minimal but expression patients with averting calf about but the
00:02:23
brutally overestimated their driving a bit so one of the like side it's that the study was
00:02:30
how good are you at driving and a hundred percent of the over it's um a
00:02:35
kind of retarded themself of as being excellent drivers ninety two percent of the mini malls
00:02:41
compared to between seventy five and eighty percent of the i mean pay and they have
00:02:46
and this is probably to do with the fact that the disease causes some degree
00:02:50
of front allies stations so lack of insight into what you're actually capable of doing
00:02:57
it also especially in countries where um have fees paid for
00:03:02
and um uh important effects it financially in employment
00:03:06
status this is an interesting study by just but judge
00:03:10
showing that patients with roses and a history over the padding castle uppity
00:03:16
our worse off in term of their employment status and they are also worse off in terms
00:03:22
of their financial status compared to patients what's the roses with no previous history about putting careful
00:03:29
in this uh it especially in countries like i say we're this is relevant to obtaining here
00:03:34
obviously reflects on the natural history of a patent give up servers is it's
00:03:41
and another interesting observation is the this is more true
00:03:45
just showing it but there's also all german data this
00:03:49
is more true for blue collars compared to white colours
00:03:53
and i think there are two potential explanations for this
00:03:57
one is that white callers may be a for sure in the shower study
00:04:03
better educated and so they may be able to compensate a bit more compatible colours
00:04:09
but also another possibility is that there are other aspects to a pattern can follow up
00:04:14
the and of course these might affect people who do mind work more than white cops
00:04:22
and a virtually any degree of a part in careful up at the two a bit
00:04:28
more likely to fall in the course of your disease
00:04:31
and to enjoy yourself which is pronounced tickle me very relevant
00:04:35
and of course and it makes a your family and the people around you suffer to some extent this are
00:04:42
i'm old data over our own measuring um uh
00:04:47
what's called a caregiver burden infantry and number off
00:04:51
questions are asked to caregivers and you can see your uh that the
00:04:56
level of involvement the suffering workdays lost and so on and so forth increases
00:05:02
by degree of uptight again careful up at the firm i mean eh it to minimal to cover it
00:05:09
and the fact uh when when a patient has an episode over
00:05:14
the padding careful uppity their problems is changes dramatically it it marks
00:05:18
and moment in their course of lead to disease uh which is very significant this whispered shown
00:05:25
in a seminal paper by bustamante ninety nine
00:05:29
uh you uh yeah showing that a mortality at
00:05:32
one year after an episode of over the padding catalogue is fifty percent three years turns seven percent
00:05:39
and it was confirmed um on a very large
00:05:42
a danish cool words some uh ten years back
00:05:47
so it is for sure a disease that we should be worrying about that we should be working on
00:05:53
and we define it i think the most important thing to start off thinking what we should go about
00:05:59
doing and how we should go about managing the disease is agreeing on what we call a padding in careful
00:06:05
and two thousand and two where uh when the uh uh guidelines uh published
00:06:13
were published in uh by the uh world congress of custom technology a bank of up the
00:06:19
uh it was defined as a
00:06:21
set of neurological in psychiatric symptoms associated
00:06:26
with liver failure and war for systemic shot
00:06:33
um six uh we've had a joint documents
00:06:36
from easily in a s. a dean twenty fourteen
00:06:39
this uh past your uh guidelines came out in italy and that the french
00:06:45
guidelines are fresh off the press and the definition in all these documents has changed
00:06:51
in twenty nineteen i didn't have a lot but the is a set of neurologic and psychiatric symptoms cost
00:06:58
by liver failure and or shop and this is um
00:07:02
one word but it's an important word because it kind of
00:07:06
i wouldn't say it's all spat it tackles
00:07:08
a problem which was beautifully highlighted by harold call
00:07:13
in this vignette in nineteen seventy seven you see here is guy yes
00:07:19
so roddick and uh he's got a societies and he also had one where he was holding a bottle of wine
00:07:25
and is clearly being run over by a truck and a
00:07:28
smart habits our just jumps off the ambulance in these things
00:07:33
it looks like a padding calm and it does look like a protocol matt and
00:07:37
it is a set of neurologic and psychiatric
00:07:40
abnormalities associated but not caused by liver failure
00:07:46
so so now we're getting round to accept that this is
00:07:50
a disorder of largely a specific neurological and psychiatric signs and symptoms
00:07:57
and in order to call this disorder apart again careful up at the there
00:08:02
has to be some form of attribution trips so we've got to convince herself
00:08:07
that this has been caused by live it's it's and i believe
00:08:12
that uh air show aspect of this attribution process easy among emission
00:08:19
and i i'll i'll go back and to what reggie if um was saying this is that
00:08:25
a very nice a paper uh several years back
00:08:30
where the emails but also at the the l. n. capillary ammonia levels were measured
00:08:36
in relation to clinical greater the padding cough up the according to west haven karate
00:08:43
and you can clearly see that there is some degree of relationship between ammonia levels
00:08:48
and the clinical great of a padding careful up at the not very type one
00:08:53
and uh this is the case for virtually all metabolic and careful offices
00:08:58
every die but all ages knows for well that hyper try cynical now
00:09:02
has an onset for very different levels of to pose in different patients but you wouldn't find one that the taller just
00:09:09
which suggested to not measure prove cause which is why i am actually convinced that should
00:09:14
we should keep measuring i'm yeah because it gives us a feel for what's going on
00:09:19
and there's also another very important aspect this slide is often
00:09:23
cues you see i've marked one patient at the bottom there
00:09:27
was a great for west haven and has no minimum yeah that norman ammonia levels and everyone says
00:09:33
you know i'm always use less because there's one patient and calm i would normally ammonia
00:09:38
not a guideline say exactly the opposite if you have a patient was clearly confused
00:09:43
clearly does orientated or even in a coal mine and he has norman ammonia levels
00:09:48
he doesn't have enough a padded failure or enough for
00:09:53
the system enchanted to justify it working diagnosis of attacking careful
00:09:58
and this is another very very important change in the overview of the disease over the past few years
00:10:05
and i just confirmed this with a case that and a colleague of mine who's
00:10:09
also works in this area of research um had in the war the few months back
00:10:14
a fifty four year old a gentleman with alcohol related so roses um c. ten chop you
00:10:20
mel twenty seven um she had been admitted for
00:10:24
the factory aside does and was being listed for transplantation
00:10:28
and one night he developed um on your so chaotic dysfunction pretty fast
00:10:34
anyone set yeah off on a differential diagnosis pass we was that
00:10:39
he had me and all my ammonia levels and we were lacking because he'd been singing can it many times
00:10:44
so we knew exactly how much ammonia he normally run up
00:10:49
and very rapid onset yours okay active deterioration this is also a typical um
00:10:55
the onset of a pattern can floppy tends to occur over ours is pretty slow
00:11:00
and so she ordered a an emergency c. t. and of course the guy had of huge
00:11:04
every to not even too sure if it was a hemorrhage or any and in fact it um
00:11:10
um it was but uh he the way he died uh in a
00:11:14
matter of hours and it was useful to know what was going on
00:11:19
there are all types of yours okay attic come ability
00:11:24
that uh uh patients with some roses are extremely prone to
00:11:28
a bleeding is of course the first take specially in alcoholics and this
00:11:32
is a fairly comprehensive list that belongs to the recent italian guidelines but
00:11:37
just to mention possibly the most important um um common abilities or differential diagnosis elements of
00:11:44
the electorate i really didn't have a puppy and intoxication with alcohol and other recreational tracks
00:11:51
intoxication is with bands that is it things another cycle acted tracks these are no
00:11:55
longer listed as precipitous they're considered causes of an alternative in careful up with it
00:12:01
septic in careful up at the end of course uh where the border is between a padding can follow up
00:12:07
with the precipitated by infection and set to concur follow up with the none of us i guess really knows
00:12:13
and especially not causal misuse or vitamin deficiency and malnutrition
00:12:20
and before i move on and i'd like to show you um
00:12:23
um another um clinical case which uh was published a few years back
00:12:28
and not their potential mistake that we had in the old definition of it but
00:12:32
i think a floppy was that it was to be considered the diagnosis of exclusion
00:12:37
and of course there is no reason to believe that uh especially
00:12:41
an elderly syrup to maybe with a nash zeros these or an alcoholic
00:12:47
shouldn't have to three or even more reasons for your second to dysfunction this is very very often the case
00:12:53
so making a padding catalogue with the uh it diagnosis of exclusion was
00:12:57
difficult to it from the procedure standpoint and this is a very clear example
00:13:01
i'm off this uh issue this is um and
00:13:04
sixty year old lady with nash the roses was diabetic
00:13:08
and was first sent to my clinic in april twenty ten she was channel q. eighty nine
00:13:14
and she had a difficult to manage in careful up at the end pretty
00:13:17
high ammonia levels at a hundred and twenty seven you can see them up often
00:13:22
and here you can see a parameter that is taken from electronic of
00:13:26
photography in black that's slow e. g. activity so the higher the worse
00:13:32
and then a set of a second metric tests which is called face and the scale is at the other end
00:13:38
in in this case the higher the better so you can see that when she came she was clearly and careful catholic
00:13:45
and she had a very poor seconded to performance and a lot of slow activity
00:13:50
um on her e. g. n. over the man's we treated her and she got better and better
00:13:55
yeah and i mean generate twenty thirteen she turned up again at the very um uh right there
00:14:02
and you can see that her u. g. hadn't
00:14:05
changed much while her or a psychology had planted
00:14:10
and at that stage again we asked for cerebral imaging and she
00:14:13
had quite an answer rebroadcast surfing so clearly this one and had changed
00:14:18
from any careful uppity dominated picture would dementia dominated pictures and a few months down the line
00:14:24
she ended up in a care home and um uh she died a year and a half late
00:14:33
classification integrating this it's changed a little bit as well as some
00:14:38
kids are easier to do others are more difficult to do so
00:14:41
what now call over had padded in careful opportunity is no longer
00:14:46
west even grade one to four bodies west even grade to afterwards
00:14:51
so we need to have temporal disorientation because the old grade one
00:14:56
which was bizarre behaviour personality changes inability to subtract a lot and
00:15:02
was considered to be far too operator dependent to be compared to the cost centres
00:15:07
and to make the diagnosis so uh if the temporal disorientation is present we call it all for
00:15:14
and what we should writing the notes when we haven't at these are the verdict i didn't have a lot but the easy it's time course
00:15:21
we courted episodic if there have been no other episode within
00:15:24
six months we current if there's more than one in six months
00:15:29
and persistent if the patient has never really
00:15:32
get back to what is considered their baseline performance
00:15:37
we should also record whether an
00:15:39
episode is spontaneous or precipitated a
00:15:44
sometimes we can't isolated persecuting but when we can
00:15:48
it is important to leicester because the weaker and because some of them can be prevented
00:15:54
obviously you cannot teach people to avoid infections but you can teach them to avoid constipation
00:15:59
to avoid dehydration and to avoid some of the other person turns
00:16:05
yeah i have that try making numbers in the l. last a set
00:16:11
of guidelines uh which is good in mind you you can see then
00:16:14
to the left or to the right they are the same they they
00:16:17
they just listed by frequency in episodic or recommend in these are infections
00:16:23
we've heard about this already casting to steiner deleting diuretic overdose or dehydration
00:16:30
electra like disorders mostly hype on that train yeah constipation or unidentified
00:16:36
so all these with the exception of high punditry me out are capable of causing hyper money
00:16:41
and hype an extreme yeah we keep in there because we believe that at some stage to
00:16:46
pass the physiology of happen a tree me and hyper among union birch two calls to see
00:16:54
yeah what's not overt uh is called covert i'm not a fan of
00:16:59
this term which cannot really be translated in many languages including my own
00:17:05
uh but i know anything below a great too
00:17:10
we now call coverage which is the only minimal
00:17:12
alterations in your psychological electro physiological test with nothing clinical
00:17:18
or something chemical that we're not too sure have quantify
00:17:22
uh a wife or a husband the says he's not functioning
00:17:26
uh he behaves with the socially uh he slightly more writable also says things that we
00:17:32
can't using technical trials but people and doctors when all the patients are very good at picking
00:17:38
and while we state now is this cannot be done technically so
00:17:42
anything below grade to shoot won't be quantified with some to work
00:17:48
and uh i think reggie would agree with being very bad to worse
00:17:53
uh i like i work uh in a place where we've collected bored
00:17:57
sometimes invented every conceivable gimmick that has ever been used in this field
00:18:02
i spent many years trying to convert this into things
00:18:06
that people could using their clinics in their hospitals and
00:18:10
by and large i failed but a few years back i think we we may have got the right text
00:18:16
so you know to quantify mild forms of about income property
00:18:21
we suggest to use what we call the animal naming test
00:18:24
and this can only i guess the first test that doesn't
00:18:28
require any equipment only a stop watch or your mobile phone
00:18:34
and if you go by the bedside and you ask the patient to list
00:18:39
however many animals they can think off in sixty seconds
00:18:45
in our hands this was validated between pad over
00:18:48
and all their send danish data uh that's supposed essentials
00:18:52
in our hands if they can less less than fifteen animals in
00:18:56
sixty seconds they have a mild form of a padding careful thing
00:19:02
if they can laced less than ten you should no no you know
00:19:08
i there's met your your lesson anymore are even this late in the living
00:19:13
you'll be fine we had an entomologist who had suppose
00:19:18
isn't listed seventy six so i took my hands are
00:19:22
so is it pressure that seems to be working in italy in in denmark
00:19:27
if it is less than ten you should go back to
00:19:29
clinical examination and temporal orientation because you've probably missed an over
00:19:35
if people have less than five years of um formal education or more than eighty you
00:19:40
what three animals each so the fashions change slightly but this is only to tell you
00:19:45
but there's a limited effect of age and limited effective education which is very
00:19:49
reassuring because most others i commit to test suffer from big education and age effects
00:19:57
so uh i now more than fifteen animals now what i didn't have
00:20:01
a lot of the orientated for time and space less than fifteen animals covert
00:20:06
uh these are annotation for time and or flapping three more some young
00:20:11
people retain orientation for time and they flap we still call these avert
00:20:16
uh i didn't take it for time and space with a glasgow
00:20:19
coma scale of over a great for me less than a great for
00:20:24
so this is nice and easy we can do it we can write
00:20:27
it down together with the precipitous and the time course of t. t. c.
00:20:31
it is important because we using can follow up with the the diagonals are cute but failure
00:20:37
we take a lot of time being very precise about many things and i think
00:20:42
doing this in a systematic fashion in the notes is important in is easy useful
00:20:48
um i think that treatment any episode over the pattern can
00:20:52
follow up with the beats pointing user precipitated should be actively treated
00:20:57
in every set of guidelines we write that grades three
00:21:00
to four should be probably transfer to the intensive care
00:21:04
you need only with very very rarely do this i don't know um how you do this uh here
00:21:10
uh i believe in the u. k. you do that much more and so uh
00:21:14
does germany and several other countries i believe it's also structural aspects to hospital manage
00:21:21
and after an episode averted padding in careful up at the secondary profit access
00:21:25
should be instituted and this should be with a non absorb herbal that sucker right
00:21:32
with a view to obtain two to three soft stews birthday some patients need very
00:21:37
little send patients need a lot so we have to teach them to tie trait
00:21:44
a a a patient has a second episode over parking careful uppity within six months
00:21:50
it is recommended that the facts i mean it's hard it
00:21:54
and this is the way uh recommendations have retained uh the uh
00:21:59
well known a re faxing trial which was published almost a decade ago new england journal of medicine
00:22:06
it was originally designed to be faxing mean against placebo
00:22:11
and it was clearly shown a two
00:22:13
or reduce recurrence and hospitality station time but
00:22:17
between seventy to eighty percent depending on the centre of these patients were ready online too
00:22:23
so the outcome was felt to be that the
00:22:26
addition of a facsimile was useful in preventing because it's
00:22:33
of minimal and cover the paladin careful opera t. is not routinely recommend it
00:22:38
that can be easy to do it on a case by case basis
00:22:41
so this is a very weak recommendation but also one that lets us free
00:22:46
i can see why if the patient comes in and reports not
00:22:50
functioning very well maybe you're not in a position to do specialised test
00:22:56
you cannot try the course of a non observable dissect a ride if it works you will have
00:23:02
um both the diagnoses and the effect of treatment this was a written in
00:23:07
nineteen sixty three in one of the first editions of sheila sure looks book
00:23:12
a a good course of ammonia lowering treatment uh would
00:23:16
solve the problem and in some instances also provided that knows
00:23:22
the usual uh as a it has already been thinking
00:23:26
painted too bright professor portion is kind of a current
00:23:29
or persistent h. these are really difficult to treat patients
00:23:35
and by and large they are patients would be chance um
00:23:40
cool tend to have many groups of overt uh many hospitality
00:23:45
stations over time in tend not to be well in between
00:23:50
they are also all the patients that often have motor
00:23:54
aspects uh uh these are not very easy to measure
00:23:59
they look like parkinson's they tend to have paradoxical
00:24:02
reactions to uh and the parking zone and medication
00:24:06
i've had now collected maybe ten or twelve cases that have come through urology
00:24:13
in set on anti parking so means having gone terribly
00:24:16
wrong and then uh ended up coming to us for reassessment
00:24:20
yeah yeah shall submit additional uh is of course uh an
00:24:23
option in not it's not always a possible and not always safe
00:24:28
yeah it seems to be the largest and most uh interesting series about chant to be to ration
00:24:33
is this one which was published last year an american journal of custom technology with the technical cap
00:24:39
uh and that they had a a really really a remarkable
00:24:44
uh reductions in uh both the length of hospital association and the number
00:24:48
of occurrences in these patients can um um with very uh and well before
00:24:56
it is also an area where a out guidelines a set us free
00:25:02
to use their x. mixtures and also drags for which the evidence
00:25:07
is not the strongest cities for non observable by saccharine sun on observable uh antibiotics
00:25:13
i'm referring to tracks like lola uh tracks like so doom bands away which
00:25:20
is of course very useful when this is associated with a high point three yeah
00:25:25
and maybe this will also be the place where all this new tracks uh
00:25:28
would be relevant and helpful and it's also the place from the traditional measures
00:25:33
and nutritional measures have been a tradition in a padded in
00:25:37
careful operating they make sense from a pass a physiological standpoint
00:25:42
they they check sure about nutritional effects having a real positive
00:25:47
uh effects on about a careful up these very very poor
00:25:51
so i don't really think we are truly justified to
00:25:56
do things as we do we need the as removing
00:26:00
uh animal protein from the dialectic specially without checking how
00:26:04
much protein patients uh end up having is an intake
00:26:08
and um when the the the idea of replacing a animal protein we
00:26:14
terry and vegetable protein like i say makes a lot of sense from the past the physiological standpoint
00:26:21
but this that these are scattered their case series their case reports so we have to be very very careful
00:26:27
a specially because i'm the only
00:26:31
way to reach a inadequate nitrogen intake
00:26:36
uh by the placing animal protein would dietary and vegetable protein is
00:26:41
often to add branched chain amino acids in these in most european countries
00:26:47
uh i neither listed as starks nor prescribe also day are very very expensive treats
00:26:54
that was the thing that is there are probably true
00:26:58
on the other hand about nutrition and patted incur floppy
00:27:02
is that if you eat more often then three times a day
00:27:06
your conceivably more likely to um attain a positive nitrogen balance
00:27:13
you can see there this is an old study on the b. and j. from the left
00:27:17
to the right patients having three meals a day for meals a day or six meals a day
00:27:23
and you can see very obvious effects of twenty for our
00:27:25
nitrogen balance and the number of patients with positive balance so
00:27:30
for those patients who can tolerate it we suggest
00:27:33
that they split the tighter in taking three main meals
00:27:37
and then one snake in the morning one snack in the afternoon and one snack before going a bit
00:27:43
and these are not patients you wore no better than me that uh
00:27:47
sometimes they can't do this so if you have to insist on one snack
00:27:51
maybe it is a good idea to wean insist on this before
00:27:55
bed snack because then you break the long interval between dinner and breakfast
00:28:00
where they're very likely to move from a society to fasting metropolis
00:28:07
so the recommendations for uh if i can get right up at the at exactly the same
00:28:12
uh as tools for general nutrition zeros is except that or branched chain amino acids
00:28:18
may yeah that maybe uh allow the recommended nitrogen intake to be achieving patients what
00:28:23
truly intolerant to directory animal protein which are re or a few and far in between
00:28:31
so before i finish off i'm just a a little bit about the sleep wake abnormalities
00:28:36
and padding can follow up with the answer roses this has been an interest of mine
00:28:40
um for a very long time and i just mentioned um a couple of
00:28:44
uh things that uh maybe useful to learn from sleep which meant to see
00:28:50
and it's a disturbance in c. roses was first described
00:28:55
by should assure looking fifty four in a very famous
00:28:58
'kay series where comatose i'm very civilly in careful
00:29:02
about the patients also exhibit it's cheap leaking version
00:29:05
so all the slept in the daytime hours and they were often uh awake now
00:29:11
there was very little in the literature for a very long time and actually came to the fore again
00:29:17
in the very first quality of life study and tightening
00:29:20
careful operate the by turn of egg in nineteen ninety
00:29:24
and you can see here patients are split uh by uh the presence of minimal pattern careful up the
00:29:31
the green ones and nobody been careful up p.
00:29:34
b. red ones and have the individuals are in blue
00:29:39
and you could see out of uh several
00:29:42
quality of life items that sleep schoolers very high
00:29:46
patients with a mild forms of a paladin careful up at the beginning with
00:29:50
c. roses with out of padding can't property they complain of sleep with disturbance
00:29:57
and and the the yeah the you should that that the uh makes this
00:30:01
clinically relevant in terms of its past physiology is that as you know for well
00:30:06
most sleep inducing medications our country indicator contra indicated
00:30:11
in these patients and they often have paradoxical effect
00:30:13
so it's useful to try understand why they don't sleep so we can
00:30:16
try and find more rational and uh and possibly non pharmacological to just
00:30:23
so and over the years uh we have
00:30:26
worked on the phenotype mostly we disturbances services
00:30:31
on the relationship with h. e. which is not that obvious uh some mechanistic inside
00:30:37
saying we've tried to borrow from sleep science
00:30:40
some tools both for diagnoses and for treatment
00:30:46
so i have the phenotype see what phenotype in so roses regardless of academy calf about it
00:30:53
is characterised by very high prevalence having some yeah much more so than in patients with other
00:30:59
chronic liver disease such as keep the disease or
00:31:02
um i'm part failure they have trouble falling asleep
00:31:07
they wake up many times they have delayed sleep wake athletes regardless of etiology so it's not
00:31:14
only alcohol or drugs users that have these phenotype and they tend to be sleepy in that day
00:31:22
at that phenotype of sleep with these terms in the time in careful opted for sure or the one
00:31:28
bit that is strongly related to the padding can
00:31:30
flop at the ease excessive daytime sleepiness these are sleepy
00:31:35
slowly patients that are very easy to fall asleep in sleeping is is picked up like sh
00:31:42
i was a very uh impressed um by uh when i saw all
00:31:48
uh in a study of or amino acid
00:31:50
challenges about a c. but now many years ago
00:31:55
or achieve has mentioned that there is a possibility to induce hyper morning yeah
00:31:59
in a controlled fashion by ingesting the equivalent
00:32:03
of half a litter of plot in amino acids
00:32:07
and it's there it's horrible thing to drink i've i've had many
00:32:12
and and it's also a um we've we've tried to flavour it with
00:32:16
banana chocolate and all sorts but it does taste plot in whichever way
00:32:21
you do it any in order to have the equivalent of a gastrointestinal bleed you have to
00:32:25
dilute it quite a lot so it's not a pleasant experiments but they managed to probably down
00:32:31
and then you see there eh in the white circles is healthy volunteers and
00:32:37
in a uh in the black these patients
00:32:40
after three to four hours since drinking this mixture
00:32:45
these are capillary ammonia levels you can see that both
00:32:49
impatience and in healthy volunteers i'm only increases very rapidly
00:32:54
because this is nothing to do with liver disease but uh the mixture is absorbed
00:32:59
in the small intestine amino acids are also dies and so there's a peach mould
00:33:03
which occurs both inpatient and healthy volunteers and then you see that i'm only i'm
00:33:08
goes down fairly fasting healthy volunteers and stays up for quite a long time patients
00:33:14
and what i did this for entirely separate reasons they have volunteers
00:33:19
they couldn't keep their eyes open including myself professor i'm audio professor
00:33:24
mankind i got everyone in the department to drink this thing and
00:33:27
all i complained about was that they were feeling terribly sleepy so
00:33:31
in like in the second half of this experiment with the measures sleepiness with uh
00:33:36
scale uh which is called the carolyn stress sleeping a scale in here you can see only healthy volunteers
00:33:43
on a day where they had the standard breakfast with no coffee or tea and on the day when they had the mixture
00:33:49
and you can clearly see that they're much sleep your when they happen mixture
00:33:53
and the peak of sleepiness is roughly the same time of the ammonia p.
00:33:58
and the same also applies to patients except that patients start off
00:34:02
with higher ammonia levels they're probably a bit more used to it
00:34:05
and so the difference on the the normal breakfast day in the um or amino acid channels today
00:34:12
is a bit smaller so i think sleepiness is a very good proxy for padding careful with it
00:34:19
um if we look at what happens in the brain of raw
00:34:24
which have been treated with the uh an ammonia diet when they sleep when you sleep deprived them
00:34:30
and this is a very interesting experiment if you sleep deprived an animal
00:34:34
the uh at the end is in in their cerebral spinal fluid goes up
00:34:38
slow yeah then is in the store to mediate what we call um
00:34:42
the home is static response to sleep deprivation so goes high into the forest
00:34:47
and you can see there in grey norman rats ending black rocks that have
00:34:52
been cheated with a hyper m. and guided both groups have been sleep deprived
00:34:56
and you can say that the agendas in response is
00:34:59
much more attract in mass speaker in the ammonia treated rats
00:35:03
so my impression is that both animal models and patience show
00:35:08
that the uh sleepiness uh that we seen patients with padding can follow up with the is
00:35:15
sort of a favourite sleep precisely way transition so they're easy to move from wait to see
00:35:21
and they're also very easy to move from c. to wake sold we're starting to um think that
00:35:26
maybe excess if a daytime sleepiness and sleep fragmentation
00:35:31
are two aspects of the same bus physiological pop
00:35:35
any beep if we go back to the ground and they they they
00:35:38
you see that the same or the same levels of a impairment in there
00:35:43
uh see quality of light item are also observed in the under this act
00:35:48
so it may be that we're looking at two parts of the same prop
00:35:54
and in this case it seems in twenty seventeen the nobel prize uh
00:35:58
uh for physiology was given to three sleep scientists to our were largely responsible
00:36:05
for a car find the mechanism serves a cajun with me city there's is being and phenomenal
00:36:11
i'm a translation of a sleep weakening specially secured in research
00:36:17
so i think it's a is it smart it's wise to borrow from this
00:36:21
type of research and we try to borrow from the point of view of diagnoses
00:36:26
and a slip scientists and people working sleeping driving
00:36:32
and i use it test which is call uh the second mortar vigilance tasks
00:36:38
test which is substantially different from the test to use for putting catalogue
00:36:43
any space and a very large number of reaction times where you're not too worried about
00:36:49
the reaction time per se how slow the patient is but how fast they tire and how
00:36:55
well they recover show you do it for long enough time that you can see the time code
00:37:00
and we do this in a large group of patients with some
00:37:02
roses for purposes of both measuring sleepiness and their ability to try
00:37:08
and then we were able to show that by and large even when they did not have a pet i think i thought that the
00:37:14
yeah they did reasonably well still worse than healthy volunteers
00:37:19
when they did have have padding can follow up with the the
00:37:21
did very badly on this test expression in terms of recovery time
00:37:26
an interesting he we were not able to show that the
00:37:30
patients who perform badly on the test where the ones that got
00:37:34
findings and where involving draw traffic accidents but the ones who were not driving
00:37:40
so sleepiness is probably picked up either by a
00:37:43
doctor or a family member it is perceived as dangerous
00:37:47
so these patients has already been isolated as dangerous drivers which makes the test even more interesting
00:37:55
and uh we have also barred from sleep wake science in terms of treatment
00:38:01
asked a break sciences like uh what they call sleep we
00:38:05
cagey measures uh it's specially in relation to light and dark
00:38:10
two mealtime mean to exercise timing so we try to implement some of this and
00:38:16
one of the things that we tried both in in patients and in our patients has actually been light therapy
00:38:23
and a light is the one signal that the
00:38:26
brain understands as signalling day get into a activation
00:38:32
and sell we and set up a a one off
00:38:36
to single rooms in our what in part of that
00:38:40
with the type of lighting equipment that a
00:38:43
sleep scientists used to correct delayed sleep phase syndrome
00:38:47
or object light east is what happens to you when you go to singapore
00:38:52
and you can get out in the morning and we all know for well
00:38:55
but if you manage to get yourself ah when you see the light in the morning in singapore
00:39:00
in a few days then you synchronise yourself to the local environment and you kind of your keyword
00:39:06
but of course if you haven't travelled singaporean you have the same
00:39:08
phenotype there's nothing you can do other than other than getting light artificially
00:39:14
and this work reasonably well in the world but we had probably
00:39:17
put ourself in a very difficult position because these patients over six
00:39:21
had been admitted into hospital so my hoping that light would really changed or
00:39:26
sleeping patterns and their pattern can from up at the was a bit high
00:39:30
so we've moved to um um a kind of feels that this in this area
00:39:37
yeah we give them my readings light boxes and now
00:39:40
there's other tools that have become available that are like classes
00:39:43
because the issue with light boxes is that you have to sit in front of them in the morning
00:39:48
well i'd classes uh that you can where they have uh we got at the back that switches them on and off
00:39:54
and they give you roughly the same amount then you can of course
00:39:57
use them while you're having breakfast brushing your teeth and getting ready to work
00:40:01
and we get quite a large um i don't study uh in a group of patients with prime rib your
00:40:07
ecology i'd isn't in a large group of patients it's
00:40:10
roses and we gave them a light boxes for three weeks
00:40:15
uh and you can see uh uh some
00:40:17
sleep with parameters at baseline invite and after treatment
00:40:22
uh for two weeks in grey positive effects more so in primary be recalling jacket
00:40:28
but also a little bit into roses and i think that
00:40:31
given this is completely side effect free education friendly disparity problems
00:40:36
and i guess i thank you all very much for your
00:40:47
very much so
00:40:48
for them because such good new tools possibly to move
00:40:53
to so just well what position by member from people
00:40:56
um might as a possible new therapy for for for these patients who were to be problems
00:41:03
this point point impolite to as many for the menu yeah so this is open for discussion please go on
00:41:15
it will also include a presentation is very interesting and
00:41:21
that's exactly what you see is from the perspective of like
00:41:27
your presentation uh my question is that you uh generate you
00:41:31
develop the most so to to find a convert a ah
00:41:36
i've taken setup c. right on but you try not mm be
00:41:40
used uh to uh we used to after the patient something like
00:41:46
whole what you've told you seven minus seven forty six minus seven so how does it compare this
00:41:53
have you compare this to hold candidates which ones
00:41:57
but a choose your of conversations and the um
00:42:01
have you posted about the accused level and the social status all this
00:42:08
yes that's my questions and i thank you very much it to view you've
00:42:12
touched on on two extremely relevant aspects which i kind of got lost in this
00:42:18
model of information so what aspect is different a
00:42:22
an cognitive domain side believe so if you use subtraction
00:42:27
uh no and we use animals you could call
00:42:30
semantic fluency uh as a as a cognitive area and
00:42:36
what we actually do on a daily basis in our clinic we haven't your psychologist
00:42:41
and we tend to do a fairly extensive evaluation and
00:42:46
sat tests we want to be abnormal to convince yourself
00:42:51
that the patient has a party can can follow up with the others who
00:42:54
want to be either of normal abnormal to work out whether they have something else
00:42:59
i do not believe that calculus has a big role in
00:43:03
the neural cognitive diagnosis of a pattern can follow up with the
00:43:06
for sure at attention does n. x. specially divided attention
00:43:11
that's so because you can measure attention at different levels
00:43:15
uh and divided attention is essentially the ability to switch from one task to another
00:43:21
and that's very profoundly impaired very early so i i agree
00:43:25
with you that attention is an area that should be convert
00:43:29
there are as that are completely and passed by pattern careful uppity including
00:43:34
vat abilities which is why we get nowhere by just talking to that
00:43:39
and memory except for working memory so if a patient has a memory
00:43:44
sure you have to worry that their demented and not in capital thing
00:43:48
so the the usual or what's abnormal in in your psychological scheme
00:43:52
is very important and the second night now or forgot your second question
00:44:00
yes
00:44:02
dual dual aspects on this yeah yeah i um when i didn't set committee was first introduced in the
00:44:10
area are used to say number connection test a. is abnormal if you take more than twenty four seconds
00:44:16
now there are the age and education adjusted
00:44:20
norms for almost every country for almost every test
00:44:25
and we also started measuring something else which is called cognitive reserve
00:44:30
a a new or psychology is not all that if you have a lot of
00:44:34
hobbies if you have a very active life if you walk your dog play sports
00:44:39
and you have had format you suffer much less than somebody
00:44:43
with the same troll mad that doesn't have as much stimulation
00:44:47
and now uh there are tools that are not fantastic but the existence
00:44:52
eh to measure what we call cognitively here so what
00:44:55
we've built up in a life that allows us to compensate
00:44:59
and we've also accomplish this study on this uh on on it very simple to which was developed in italy
00:45:05
and it is shown to be very very relevant to your psychological performance
00:45:12
maybe what we would probably questions might want to ask you questions would lose the toes adjusting the exercise
00:45:18
preparations the purpose of property can be up to can you comment to be told that
00:45:23
i think they they have i i i have an idea that maybe you can help me develop
00:45:29
i think the timing of exercise in on top of exercise per se
00:45:36
might be much more relevant to obtain careful opportune
00:45:39
been exercising general in this is because a room
00:45:45
besides like dark signals fruit cues
00:45:49
movement is the one small time give
00:45:53
or that the brain understand so i think if we put in there
00:45:57
if you put them in the right light dark environment if you feed them at
00:46:00
the right time if you move them at the right time you you may find anything
00:46:07
'kay
00:46:11
which you probably stupid reprogram it you put your to do so it would be one
00:46:16
that's true for um but i have a question we're going
00:46:18
very particular suffered but you the packets i'm used to parkinson's
00:46:23
by coincidence parkinson's yes because this is true only research should
00:46:28
as to how do you explain your would be to use
00:46:32
how to use you that it holds regions of the products are response between okay yeah yeah yeah
00:46:40
the off um
00:46:44
but trying to answering dates but first of all we're not
00:46:47
very good at measuring a motor uh impairment independent careful up the
00:46:52
one of the tests we use which is called the city adopting where you
00:46:56
ask the patient to dot the as fast as they can and maybe useful
00:47:01
and has been used to shoulder the packing some ism of a party can can follow up with the
00:47:06
he is slightly different from parking sun in the
00:47:09
sense that it disturbs movement enunciation so they have travelled
00:47:13
starting a movement in so if you make them repeat the
00:47:15
same movement many times you can obviously yeah highlight the problem
00:47:20
they they based forms of multiple to think of a lot of the
00:47:25
ad called a patted my little petty and can cool up to par pizza
00:47:30
and then maybe fifty sixty cases in the literature
00:47:34
they all males and they all have major shuns
00:47:38
they have normal city barrel in spine yeah emmett ice
00:47:43
and not necessarily very high ammonia levels which makes
00:47:47
us think that something is going to this chance me
00:47:51
the the thing believe that if there's some old italian data to suggest that you told me play animal
00:47:58
and basically it and i call myself once with a very difficult case because
00:48:04
we we had the guy who was on a transplant list and became paraplegic
00:48:09
and he was also very often careful plastic so
00:48:13
um basically they ask us that to make sure
00:48:18
to to try to understand whether by transplanting him a we were going to solve his
00:48:23
lever problem in these puppy chow or just easily the problem and he was the fourth
00:48:28
uh the patient we departed milo putty to be transplanted the first three were transplanted in germany
00:48:34
and we were successful but essentially easy situation where that
00:48:38
a differential diagnosis easy but you you only have to exclude any conceivable neurological disease
00:48:45
and one thing that can help ease if you use a a every to
00:48:49
look like a a fax you mean like two rows lorna bland to change
00:48:54
sometimes you can see some improvement the patients report some improvement in
00:49:00
so you become a bit more confident that what you're seeing is
00:49:03
and and then there is the old the new england the town trouble keeping
00:49:08
i had some experience in england of using double clicking in these patients and uh
00:49:14
yeah you need telly we can't uh so i i have the you need to the experience
00:49:20
uh_huh
00:49:24
he was he it was yeah yeah if ever in style experience because the shirt and randy and he
00:49:30
said do you believe this guy has this disease and i said i don't know because i've seen one
00:49:34
i ring around then i ran current vice amber and i sent out all
00:49:38
the data and they transplanted human uh six weeks down the line he was
00:49:44
back to work oh
00:49:49
x. ascii uh_huh what what what
00:50:01
uh_huh
00:50:06
uh_huh
00:50:10
oh
00:50:15
but i am so thankful to talk to stick to very clinical based question
00:50:21
so we we so we very often have situations you have the elderly ex alcoholic
00:50:27
patients with slightly elevated ammonium levels but not too
00:50:31
high if everybody's talking about plastic inc incapable physique
00:50:35
and then everybody's trying to figure out um easy just to be mad easy copy then we could
00:50:40
beginning easy starting to get to mend was it something where with the transplant will solve all these problems
00:50:47
so just from a clinical point of view which are
00:50:49
the best and easiest test without having to involve complex
00:50:55
it's like magic test what would you would always well they it without
00:51:00
involving any set committee tests a good good course of ammonia lowering treatment
00:51:05
and in time uh one aspects that we didn't touch upon the
00:51:10
back knows everybody can cover up this time is is very useful
00:51:14
if you can show that they have some degree of memory disturbance this
00:51:19
normally goes in favour of concomitant disease any these instances we always to say that any matching
00:51:26
possibly e. unless country indicating them and enema i also looking at the ponds
00:51:31
and the money larry bought these because you were saying you know an example
00:51:39
but it's
00:51:41
so what do we know from any imaging plaintive you related with subplot at the end
00:51:47
does correlate with the clinics so what we see in just sleep areas of the brain
00:51:52
to the core like that with v. c. would sleep alterations patients without its ability
00:51:57
well large we do not use a imaging uh to conform
00:52:03
or disprove a diagnosis of of putting can follow up with the
00:52:07
for sure the changes you see in basal ganglia impatience was roses which are
00:52:12
often seen regardless of the presence of clinical the padding follow up with the
00:52:17
there are some relations with the motor aspects that's
00:52:20
for sure and probably express some degree of manganese toxicity
00:52:25
which is very difficult to measure at some stage we got involved with the um
00:52:30
how do you call a and the the work doctors the doctors to do preventive medicine to try
00:52:35
in setup tests that i use for manganese intoxication as we got nowhere
00:52:41
but by and large we use imaging especially in that we transplant face to exclude that
00:52:46
these patients to not have anything else significant that would make them pay it after transplantation
00:52:55
not with
00:52:59
you know so you have someone that would lose them all between c. b. s. and i don't want you
00:53:05
and do you see what he does all the work of formula below to stick to sleeping on
00:53:12
okay that's a very interesting question and all men that's only
00:53:19
is not the sleep former it's the dark foreman so many long range
00:53:24
gives you a feel for where the phase of your internal clock yes
00:53:29
not your sleepiness although i'll uh if you and i mean it's
00:53:34
the high levels of of syntactic melatonin diseases small supportive a cafe
00:53:41
these patients here that we um we we measured
00:53:44
a melatonin both in plasma and in you weren't
00:53:48
and the contrary to what we expected melatonin metabolism is preserved
00:53:54
even in advance the the disease it becomes abnormal in only over night
00:53:58
when melatonin levels are very high in child c. or actually patted fail
00:54:04
and know that oh he's he's in in any interesting aspect of their
00:54:09
seat wig regulation but i wouldn't say plays a major role in sleepiness
00:54:16
oh
00:54:20
it's still a bit but controversial topic is lots of
00:54:26
people still measuring pneumonia without the bridge and do
00:54:30
not have any signs of open you to use on
00:54:34
so i personally tell them i do not think there is enough evidence to do read bought i would
00:54:41
like the expert's opinion maybe with the new the total going to talk to you for that data would come
00:54:46
what is there no rule of measuring the moon known symptomatic
00:54:50
patients not the if the short answer to that is no
00:54:54
yeah what i would say is also i don't know whether i said this or or rent is it said it or not
00:55:00
and d. that there are several problems with pneumonia that measurement issues with pneumonia
00:55:07
lead to force positive so when one measures them
00:55:11
on yeah they should remember that if to blight doesn't
00:55:14
go we nice if it's not measured within ninety
00:55:17
minutes and a you can have a falsely high values
00:55:22
uh and this is it happens a lot in italy sometimes we have a
00:55:26
home k. have so somebody goes with the node fee at that and that
00:55:29
collecting glass and then puts them in the back of the field and that brings them all to the lab and they're all hype from
00:55:36
but there are virtually no force negative so if you get
00:55:39
the normal ammonia level whichever way you've done it that's true
00:55:43
so i would say that in the context of mental confusion it has an
00:55:47
enormous negative predictive value and i wouldn't measure if if a patient is known sentiment
00:55:56
and so i would like to think of the thank you
00:56:06
i'm not too closely simple to please remember that you have
00:56:10
your your sophisticated opens come to take a look to think
00:56:15
again both speakers to compute boom give most is very very nice
00:56:20
representations of all of you for participating in most constant once again

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Welcome
Annalisa Berzigotti, Berne
Nov. 28, 2019 · 6 p.m.
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